Design strategy and research progress of multifunctional nanoparticles in lung cancer therapy

ABSTRACT

Introduction

Lung cancer is one of the cancer types with the highest mortality rate, exploring a more effective treatment modality that improves therapeutic efficacy while mitigating side effects is now an urgent requirement. Designing multifunctional nanoparticles can be used to overcome the limitations of drugs and conventional drug delivery systems. Nanotechnology has been widely researched, and through different needs, suitable nanocarriers can be selected to load anti-cancer drugs to improve the therapeutic effect. It is foreseeable that with the rapid development of nanotechnology, more and more lung cancer patients will benefit from nanotechnology. This paper reviews the merits of various multifunctional nanoparticles in the treatment of lung cancer to provide novel ideas for lung cancer treatment.

Areas covered

This review focuses on summarizing various nanoparticles for targeted lung cancer therapy and their advantages and disadvantages, using nanoparticles loaded with anti-cancer drugs, delivered to lung cancer sites, enhancing drug half-life, improving anti-cancer drug efficacy and reducing side effects.

Expert opinion

The delivery mode of nanoparticles with superior pharmacokinetic properties in the in vivo circulation enhances the half-life of the drug, and provides tissue-targeted selectivity and the ability to overcome biological barriers, bringing a revolution in the field of oncology.

KEYWORDS:

• Nanoparticle
• lung cancer
• liposome
• targeted therapy
• inorganic nanoparticle

1. Introduction

Lung cancer is one of the cancer types with the highest incidence and mortality rates in the world [1]. Its histological classification mainly includes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is the most common type of lung cancer, accounting for 80%-85%, with a high recurrence and metastasis rate [2]. NSCLC can be further classified as squamous, adenocarcinoma, and large cell carcinoma, which progresses slower than SCLC. The level of detection and treatment of lung cancer is constantly improving, but once the disease is diagnosed, it is often in the late stage, and the prognosis is poor. The long-term survival periods of patients with lung cancer treated with traditional surgical resection, radiotherapy, chemotherapy, and combination therapy are far from satisfactory. Only 20%-25% of patients diagnosed with NSCLC can be treated surgically, and 30%-55% of those who undergo radical surgery suffer a recurrence and eventually die of NSCLC [3]. The five-year survival rate of patients with NSCLC is only 16% [4].

The limitations of surgery are mainly due to the lack of a clear boundary between tumor and adjacent normal tissues. Radiotherapy is often used as an adjuvant therapy for lung cancer, and its combination with drugs can enhance anti-tumor efficacy. However, the emergence of radioresistance and radiation lung injury has limited its clinical application. Although immunotherapies have achieved breakthroughs and significantly improved survival time and quality of life, they are effective only in selected patients, and immune-related side effects often lead to serious consequences [5]. Therefore, chemotherapy is still commonly used in clinical treatment [6]. It enhances immune response by inducing tumor cell lysis and releasing tumor antigens. Clinical trials show that a combination of chemotherapy and immunotherapy can significantly improve the prognosis of metastatic NSCLC. However, chemotherapy has many unavoidable defects, such as poor tumor targeting, poor tissue penetration, and multidrug resistance (MDR) [7]. Scientists have exerted continuous effort to overcoming the limitations of current lung cancer treatment and discovering novel therapies that prolong the survival periods of patients with lung cancer.

In recent years, nanotechnology has made significant advances in tumor treatment [8,9]. Various nanomaterials have emerged as a potentially advantageous class of drug delivery systems due to their ability to alleviate poor bioavailability, poor dispersion, rapid in vivo metabolism, and drug resistance associated with drug therapy [10]. Nanoparticles can provide sufficient space and protection for drug molecules and can protect the integrity of drugs during transport in the circulation and prevent contact between the drugs and normal non-targeted tissues. Various types of nanoparticles have been explored for cancer therapy, including liposomes, polymer nanoparticles, micelles, carbon nanotubes, and nanoparticles composed of metals [11,12]. Drug delivery is mainly divided into passive delivery and active delivery. Passive delivery is based on a leaky tumor vascular system in which drugs passively targets tumor cell tissues, penetrate the vascular wall and subsequently accumulate in the tumor tissues through enhanced permeability and retention effect (EPR) [13]. Active delivery is based on molecular recognition, which leads to drug delivery to a target site [14]. A variety of lung cancer targets have been investigated, such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, folate receptor (FR), and CD44 receptor. The potential applications of nanoparticles as anti-tumor agents are gradually being recognized, and elucidating the design strategies and mechanisms of nanoparticles will contribute to understanding and development of novel therapeutic agents for lung cancer. This review focuses on progress in nanoparticle research related to lung cancer therapy to provide a reference for nanomaterial selection and experiment design and promote research into nanoparticles against lung cancer.

2. Research progress of drug-loaded nanoparticles for lung cancer treatment

Nanoparticle materials for lung cancer therapeutic delivery carriers have two main types: organic and inorganic materials [15,16]. Liposomes, polymers, and carbon-containing materials are organic materials, whereas silica, hydroxyapatite, and similar calcium-based materials and metals are classified as inorganic materials. Nanoparticles loaded with anti-cancer drugs can improve the effectiveness and specificity of cancer therapy by enhancing targeted drug delivery [17]. In clinical practice, some nanoparticles have been used for the treatment of lung cancer to improve therapeutic efficacy and overcome MDR and chemotherapy toxicity. A list of FDA-approved and ongoing clinical trials for nanoparticle formulations targeting lung cancer is provided in Table 1. Therefore, the design and development of advanced drug co-delivery nanocarriers with good biocompatibility for cancer therapy is expected.

Table 1. FDA-approved nanoparticle formulations for lung cancer treatment and clinical trials.

Nano drug type	Drug	Manufacturers	Commodity Name	Indications	Drug delivery method	Role characteristics	Clinical Translation Phase
Liposomes	DDP	Regulon	Lipolatin	NSCLC	Intravenous	Extends the in vivo half-life of DDP significantly; substantially increases the drug content in tumor tissue	Phase III clinical
Polymeric micelles	PTX	Lupin	Genexol-PM	Lung cancer	Intravenous	Improves drug solubility, stability and targeting	Phase I Clinical
Nanoparticles	PTX	Bind	BIND-014	NSCLC	Intravenous	Targeted and specific killing of tumor cells without affecting normal cells around the tumor tissue	Phase II Clinical
	Camptoth-ecin	Cerulean	CRLX101	NSCLC	Intravenous	Extend the half-life of camptothecin in vivo; increase the drug content in tumor tissues; after drug release, the nanomaterials depolymerize into chain-like polymers and are excreted in the urine	Phase II Clinical
	siRNA	Silence	CALAA-01	Solid tumors	Intravenous	Extend in vivo half-life	Phase I
	siRNA	Silence	AUT-027	Solid tumors	Intravenous	Extend in vivo half-life and block PKN3 to inhibit tumor progression	Phase I
	Albumin-bound paclitaxel	Celgene	Abraxane	Breast Cancer,NSCLC and Pancreatic Cancer	Intravenous	Promote and stabilize microtubule aggregation into clusters and bundles, thus inhibiting the normal reorganization of microtubule network	Approval
Polymer-drug couples	Camptoth-ecin polymerization pre-drug	Mersana	XMT-1001	NSCLC	Intravenous	Enhance tolerability and efficacy, longer plasma half-life and higher concentrations in tumor tissue	Phase I
Inorganic nanoparticles	Hafnium oxide	NANOBIOTIX	NBTXR3	NSCLC, Head and Neck Cancer	Intravenous	Induce differential immunogenicity, triggering adaptive immune responses and long-term anti-cancer memory	Phase III
	Silicon Dioxide-Gold	Nanospectra	AuroLase	Lung cancer	Intravenous	Maximize treatment outcomes while reducing side effects associated with surgery, radiation and alternative focal therapies	Preclinical
Others	/	Coordination	CPI-200	Lung cancer	Intravenous drip	Degeneration/elimination of tumors	Preclinical

2.1. Organic framework for lung cancer treatment

2.1.1. Liposomes

As organic compounds with good biocompatibility, lipids are ideal drug carriers [18]. Lipid carriers are available in various forms, such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and lipid drug couples [19,20]. They can load hydrophilic and lipophilic drugs, improve drug utilization, and play a role in increasing efficiency and reducing toxicity [21]. Liposome-loaded drugs offer the advantages of improving drug stability, ensuring slow release, targeting, and reducing drug toxicity (Table 2). A variety of properties can be imparted to liposomes by changing materials used in prepare them or by functional modification, such as targeted, pH-sensitive, cationic, magnetic, and thermosensitive liposomes (Figure 1) [23]. To improve the stability of liposomes in vivo, the modification of some hydrophilic groups on the liposome surface is usually required. However, hydrophilic modifications greatly hinder the close contact between liposomes and tumor cells, thus reducing the active targeting to tumor cells. In addition, conventional liposomes are easily phagocytosed by the endothelial reticulum system in vivo and lose their active targeting effect. Therefore, how to improve the active targeting of liposomes in vivo while ensuring the stability of liposomes is currently a hot research topic among scientists.

Figure 1. General schematic diagram of a novel nanoliposome for lung cancer therapy.

Table 2. Merits and demerits of various liposomes for lung cancer treatment.

Liposome type	Merits	Demerits	References
Active targeting of liposomes	Enhance tumor-specific drug delivery and avoid off-target effects	During in vitro modification of liposomes, many targeting ligands are prone to denaturation and inactivation, and the stability of their targeting functions cannot be guaranteed. Also, after liposome modification and arrival in vivo through drug delivery, changes in the size and surface charge of the drug carrier may make it susceptible to phagocytosis by the reticuloendothelial system, making it difficult to reach tumor cells.·Preparation process is difficult to industrialize	[22]
pH-sensitive liposomes	Highly targeted and pH-dependent drug release	Challenging for stability during drug loading, processing and storage	[24]
Cationic liposomes	Intracellular targeting·High load capacity·Significant enhancement of intracellular chemistry through adsorptive interactions with tumor cell membranes·Extending the circulation time of nanoparticles in the blood	Blocking the release of cytosolic siRNA due to electrostatic interactions	[25,26]
Magnetic liposomes	With magnetic fluid properties	In the presence of a magnetic field, magnetic liposomes coalesce into larger particles that interfere with blood flow	[27]
Thermosensitive liposomes	sustained drug release·temperature-responsive of drug	Excessive heating time can cause normal tissue damage·Weak targeting and difficulty in evading the action of mononuclear phagocytic system·Cannot be used for delivery of fat-soluble drugs	[28,29]

2.1.1.1. Passive targeting of liposomes

Tumors proliferate and divide uncontrollably by obtaining energy or nutrients abnormally from peripheral blood vessels, decreasing the number of pericytes with abnormal vascular basement membranes, rapidly proliferating aligned endothelial cells, creating vascular leakage, and creating conditions for the passive delivery of drugs. Liposomes can effectively deliver drugs or siRNA to lung cancer sites through active targeting or EPR effects, thereby enhancing therapeutic efficacy [30–32]. Polyethylene glycol (PEG) is used to prolong half-life of drugs, prevent nanocarrier elimination by RES system. Zare et al. designed a PEGylated liposome nanoparticle loaded with etoposide that evades the vascular endothelial system and accumulates at tumor sites [33]. To overcome chemotherapy MDR, Tian et al. prepared hyaluronic acid (HA)-coated liposomes containing paclitaxel (PTX), which have a particle size of approximately 100–140 nm [34]. After intravenous injection, liposomes passively target tumor tissues by EPR action with a retention efficiency greater than 85% due to the leaky nature of the tumor vascular system and can effectively improve the anti-lung cancer effect of therapeutic PTX. To disrupt angiogenic mimetic channels, angiogenesis, and epithelial-mesenchymal transition (EMT) and inhibit invasion and migration, Kong et al. constructed a liposome encapsulated with vincristine and diosgenin that can be enriched at the tumor site by passive targeting using two novel materials (DSPE-PEG₂₀₀₀-MAL and CPP-PVGLIG-PEG₅₀₀₀) [35]; the liposomes were able to accumulate significantly at tumor sites, inhibit the migration and invasion of A549 cells, disrupt VM channel formation and angiogenesis, and block the EMT process, thus exerting good anti-tumor effects.

2.1.1.2. Active targeting of liposomes

The active targeting of liposomes can enhance tumor-specific drug delivery and prevent off-target effects. Active targeting (Figure 2) approaches are mainly performed by the surface functionalization of liposomes with appropriate targeting ligands (peptides and monoclonal antibodies) [36]. In tumors, the massive formation of neovascularization is considered a major driver of cancer progression, and therefore tumor-targeted therapies that target tumor neovascularization have become a major research topic. Arginine-glycine-aspartate peptide sequence (RGD) is a widely available cell-targeting peptide that binds to integrins on vascular endothelial cells and does not cross-react with platelet integrins and prevalent cellular receptors. Exogenous RGD can competitively inhibit the ligand binding of integral proteins, thereby inhibiting angiogenesis and migration of tumor cells [37,38]. Wang et al. prepared redox-sensitive dual drug-loaded lipopolymer nanoparticles based on RGD-modified PTX prodrugs, which can successfully load drugs to target tumor sites and enhance anti-lung cancer efficacy and have lower level of systemic toxicity than free drugs [39]. RGD-modified doxorubicin (DOX)-loaded liposomes can selectively bind integrin αvβ3 receptors and can be degraded in an acidic environment, thereby enhancing liposome accumulation in tumor cells and leading to increased intracellular DOX release [37]. In addition, the specific targeting of αvβ3 integrin receptors by RGD is still an excellent candidate for cancer imaging, which may provide a novel strategy for clinical NSCLC treatment and diagnosis [40]. The expression of transferrin receptor (TFR) is overexpressed in lung cancer due to increased iron demand [22]. T7 (His-Ala-Ile-Tyr-Pro-Arg-His) peptide is a cell-targeting peptide with specific binding affinity for TFR and can be translocated into cells by cytokinesis facilitated by transferrin [41]. Riaz et al. formulated T7-targeted liposomes containing QUE with different peptide densities; compared with nontargeted QUE liposomes, T7-targeted liposomes exhibited significantly enhanced cellular uptake and cytotoxicity in A549 cells (nearly three-fold) and a longer sustained release in the lung (nearly 96 hours) [42]. The study of these peptide surface-functionalized liposomes in lung cancer therapy provides promising insights in lung drug delivery targeting and sustained delivery of drug therapy. Polysialic acid (PSA) is a biopolymer that plays an important role in tumor progression and invasion and naturally hydrophilic, biodegradable, and non-immunogenic, and its monomeric receptor is expressed on peripheral blood neutrophils. Luo et al. synthesized a PSA-octadecylamine complex and modified it on the surfaces of liposomes to develop a drug delivery system for neutrophil-mediated anti-tumor therapy [43]; the results showed that the liposome was recruited to tumor sites and guided by inflammatory factors and was able to deliver chemotherapeutic drugs to lung cancer cells in a spontaneous and on-demand manner, thus showing promising use in targeted tumor therapy. Compared with traditional liposomes, active targeting of liposomes can significantly enhance the therapeutic effect of drugs on target cells, but many targeting ligands are susceptible to denaturation and inactivation, which cannot guarantee the stability of their targeting function. Meanwhile, after the liposomes are modified, changes in the size and surface charge properties of the drug carriers may make them vulnerable to phagocytosis by the reticuloendothelial system (RES) and difficult to reach tumor cells.

Figure 2. Passive, active, and physicochemical targeted nanoparticles.

2.1.1.3. Cationic liposomes

Positively charged cationic liposomes are widely used as drug or siRNA carriers due to their high loading capacities and significantly enhanced intracellularization through adsorptive interactions with tumor cell membranes (Table 3), and their PEGylation prolongs the circulation times of nanovesicles and prevents capture by RES [44]. 1, 2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is a lipid synthesized with a positively charged cationic group at the head and binds to negatively charged compounds on cell membranes, enhancing the internalization and delivery of drugs to specific target cells. Cationic DOTAP liposomes loaded with All-trans-retinoic acid enhanced anti-lung cancer activity against an A549 lung cancer cell lines and anti-lung metastatic activity in an in vivo metastatic mouse model [51]. Inhaled pirfenidone cationic liposomes can target chemotherapeutic drugs deep into the tumors and facilitate the accumulation of drugs at target sites, thus reducing systemic toxicity [45]. FA-modified liposomes used in the study of Tie et al. showed considerably low toxicity due to FA modification that blocked some positive charges [46]. MicroRNA-143 (miR-143) significantly inhibits the migration and invasion of NSCLC, and its cationic liposome (CL)-pVAX-miR-143 complex, which accumulates mainly in the lungs of mice, effectively inhibits NSCLC tumor growth, significantly suppresses tumor metastasis, and prolongs survival in a dose-dependent manner. More importantly, CL-pVAX-miR-143 treatment did not induce significant acute toxicity and is expected to be an effective strategy for NSCLC treatment, especially advanced metastatic NSCLC [41]. But most cationic liposome systems have an excessive positive charge, which may hinder the release of cytosolic siRNA due to electrostatic interactions [47].

Table 3. Cationic liposomes currently developed for the treatment of lung cancer.

Loading drugs	Liposomal materials	Object of action	Liposome action	References
Unmethylated oligodeoxynucleo −tides containing CpG motifs (CpG)	1,2-dioleoyl-3-trimethylammonium-propane; 1,2-dipalmitoylpHospHatidylcholine	B16F10 model of metastatic lung cancer in mice	Protect drugs from rapid extracellular degradation and increase their uptake by lung phagocytes.	[52]
PTX	Cholesterol, stearylamine and DSPE-PEG2000 and Lipo-Cat	A549 and LLC cell	Improve PTX biocompatibility, antitumor activity against cancer stem cells, and enhance the in vitro and in vivo antitumor effects of PTX free activity, but also protect against PTX-induced painful peripheral neuropathy.	[44]
miR-143 plasmid	Avanti Polar Lipids and cholesterol	A549 cell, naked mouse	Ensure formulation stability and safety, and accumulate mainly in the lungs after systemic administration.	[41]
VRB bitartrate and Quinacrine	L-alpha-Dipalmitoyl phosphatidylcholine, DC-Chol and DSPE-PEG2000	A549 cell, BALB/c mice	Significantly enhance cellular uptake and selective accumulation in A549 cells, thus exhibiting the strongest antitumor efficacy against tumor cells and tumor-bearing mice.	[53]
Hydroxycampto -thecin and 5-aminolevulinic acid	Soybean lecithin, cholesterol, octadecylamine and medical ultrasound gels	BALB/c mice	Increase the water solubility of drugs and protect them from rapid degradation to improve antitumor drug efficacy.	[54]
FUS1 and IL-12	1,2-Dioleoyl-3-trimethylammonium propane, cholesterol	A549 cell, NOD/SCID mice	Stable formulation with higher antitumor activity and lower toxicity in pulmonary metastases.	[55]
siRNA	1,2-dioleoyl-sn-glycero-3-ethylphosphocholine and cholesterol	LLC cells, BALB/c mice	High efficiency of in vivo drug delivery to lung cells, higher antitumor activity and lower toxicity in lung metastasis models.	[56]
Pemetrexed disodium	Egg yolk lecithin cholesterol and stearylamine	NSCLC cell, Kunming mice	The slow release of the drug prolongs the retention time in the body, increase the value of AUC, improve the accumulation and relative uptake rate of the drug in the lung, and enhance the anti-tumor efficacy of the drug.	[57]
PTX	1,2-Dioleyloxy-N, N-dimethyl-3-aminopropane, DOTAP, 1,2-dioleoyl-sn-glycero-3-phosphocholine, Cholesterol, N- (Carbonyl-methoxy-polyethylene glycol 2000)-1,2-dipalmitoylsn-glycero-3-pHospHoethanolamine	A549 cell, female athymic nude mice	Induce upregulation of miR-21 targets, including PTEN and DDAH1, in A549 cells, while increasing their sensitivity to PTX; achieve tumor regression, prolong survival and upregulation of miR-21 targets in an A549 xenograft mouse model.	[58]
PTX	Soybean lecithin, mPEG2000-DSPE, and Mal-PEG2000-DSPE, Cholesterol, T7 peptide and TAT peptide	A549 cell, BALB/c mice	Enhance in vitro cellular uptake with highest accumulation capacity; improve in vivo inhibition of tumor growth.	[59]
Cisplatin and metformin	2, 3-Dioleoyloxy-propyl)- trimethylammonium DSPE-PEG2000, DSPE-PEG-aminoethyl anisamide, cholesterol	H460 cells, Female nude mice	Significantly increase tumor accumulation of the drug and inhibit tumor growth through apoptosis without nephrotoxicity.	[60]

2.1.1.4. Magnetic liposomes

Physico-chemical targeting formulation entails the use of physico-chemical methods in preparing formulations effective at specific sites. The main physicochemical targeted liposomes are magnetic, thermosensitive, and pH-sensitive liposomes. Magnetic liposomes are formed by encapsulating small (single-domain) magnetite particles in liposomes, which combine the biocompatibility of liposomes and vesicle structure with superparamagnetic properties, and are therefore magnetic controllable agents with no side effects on organisms [61]. Circulating tumor cells (CTCs), which are shed from primary tumors and into the circulation, can be localized to distant organs and thus contribute to tumor metastasis [48]. Previous studies have shown that CTC counting can be a prognostic and predictive biomarker for patients with cancer [49]. Moreover, CTC counting by EGFR magnetic liposomes can complement response evaluation criteria in solid tumors and allows the dynamic monitoring of the responses of patients with NSCLC and on EGFR tyrosine kinase inhibitor therapy [50]. In addition to being a detection system, magnetic liposomes can play a therapeutic role. Novel EGFR-targeting and thermosensitive multifunctional liposomes based on manganese-doped magnetic engineered iron oxide nanoparticles and gold nanorods were developed for efficient photothermal therapy and magnetic resonance imaging. The liposomes can selectively target EGFR-positive tumors and promote tumor destruction by laser activation [62]. Owing to the specificity of the materials, the application of magnetic liposomes to acoustic wave therapy has been investigated. Zhu et al. established chlorin e6-loaded sonosensitive magnetic nanoliposomes (Ce6/SML) for targeted delivery in external magnetic fields [27]. As an acoustic chemotherapy targeted delivery system, Ce6/SML can effectively enhance the anti-tumor activity of acoustic chemotherapy and has potential use in the treatment of deep-tissue malignancies.

2.1.1.5. Thermosensitive liposomes

Thermosensitive liposomes are carriers that enable the release of drugs from liposomes by increasing the temperature. Thermosensitive liposomes are often combined with thermal therapy to allow drug aggregation at the site of a disease by increasing vascular permeability and minimizing drug delivery to critical normal tissues during interstitial transport. In addition, heat therapy enhances the permeability of the lipid bilayer, thus promoting the release of payload and significantly improving the anti-tumor effect of drugs [63,64]. Shen et al. studied the development of a DOX-loaded multifunctional magnetic nanoparticle thermosensitive liposome (DOX-Fe₃O₄-TSL) for near-infrared laser-triggered release and photothermal combination chemotherapy of tumors [65]. The results showed that DOX-Fe₃O₄-TSL had a significant inhibitory effect on tumor growth under NIR laser irradiation without significant damage to normal tissues. Magnetic nanoparticle thermosensitive liposomes showed greater potential for laser-triggered release due to their low toxicity, good biocompatibility, and magnetic resonance imaging capabilities. Thermosensitive liposomes regulate the release of drugs mainly by the change of liposome membrane structure at different temperatures. The transmembrane diffusion of lipid-soluble drugs is strongly influenced by the changes of liposome membrane structure, thus only water-soluble or amphiphilic drugs are suitable for the preparation of thermosensitive liposomes.

2.1.1.6. pH-sensitive liposomes

Drug delivery systems enhance the efficacy of chemotherapeutic agents by enhancing targeting and controlled release, but the biological barrier of the tumor microenvironment greatly hinders the penetration of nanomedicines within a tumor [66]. pH-responsive nanocarriers offer great benefits, which are attributed to the fact that the acidic microenvironment of cancer cells attracts these nanocarriers and thus maximizes drug release [67]. Difference in pH between normal and tumor tissues has been widely used as a trigger signal for the design of delivery systems based on extracellular acid instability bonds [68]. pH-sensitive liposomes usually consist of dioleoylphosphatidyl-ethanolamine and cholesteryl hemisuccinate [69]. The overexpression of FR-β is associated with poor prognosis in NSCLC [70]. Park et al. developed an FR-targeted pH-sensitive liposome by using polyene paclitaxel (DTX) and doxycycline that enables effective drug delivery and acid-responsive release in NSCLC cells, resulting in the effective inhibition of tumor growth [24]. pH-sensitive liposome drug delivery is one of the effective ways to overcome MDR. Shen et al. developed a novel PTX/hydroxypropyl–β-cyclodextrin complex-loaded liposomes [71]. The liposome exhibited pH-sensitive PTX release and potent cytotoxicity and enhanced intracellular accumulation, which significantly inhibited tumor growth and provided a novel strategy for overcoming MDR. Although pH-sensitive liposomes can enhance drug efficacy, their stability during drug loading, processing, and storage remains a challenging research problem.

2.1.2. Polymer-based nanocarriers

A polymer is a macromolecule or long-chain molecule formed by the linking of repeating chemical units [72]. Polymers, including natural, synthetic polymers, and polymeric micelles can act as drug delivery systems that deliver anti-cancer drugs to tumor sites and enhance their anti-tumor efficacy [73]. Polymers have the advantages of reducing drug toxicity, enhancing targeting, evasion RES trapping, increasing drug solubility, improving drug bioavailability and biodegradation [74,75]. By changing the polymer synthesis material, polymer morphology, and pore size, the functional properties of the polymer can be changed and thus used in different routes of anti-cancer therapy (Table 4).

Table 4. Polymer-based nanocarriers currently developed for the treatment of lung cancer.

Classification	Loading drugs	Materials	Functions	References
Natural polymer- based nanocarriers	PTX, QUE	Cs, cetuximab, Sodium tripolyphosphate	Improving drug bioavailability	[76]
	PTX	Poly(lactide-co-glycolide), 2-HP-β-CD, Polyvinyl alcohol	Prolong PTX release, enhance drug transport efficiency	[77]
Synthetic and hybrid polymer-based nanocarriers	Cisplatin caprylate and ABCC3-siRNA	PEG-PLA, 1, 2-Dipalmitoyl-sn- glycero-3-phosphocholine, DOTAP	Imparting long circulation characteristics to the carrier	[78]
	Nucleic acid	PBAEs	Protect their nucleic acid cargo while promoting cellular uptake and endosomal escape	[79]
Polymeric micelles		Polycaprolactone, NAD(P)H: quinone oxidoreductase-1, PEG	Enhanced drug accumulation in the tumor	[80]
	DOX	PEG-b- poly(dithiolane trimethylene carbonate)	Favorable features of superb stability, minimal drug leakage, long circulation time	[81]
Polymersomes	MTX	PEG-b-poly (trimethylene carbonate-co- dithiolane trimethylene carbonate)- b-polyethylenimine	Show potent anti-tumor activity, depth of tumor penetration	[82]
	Granzyme B	Anisamide end-capped PEG-b-poly(2,4,6- trimethoxybenzylidene- 1,1,1-tris(hydroxymethyl)ethane methacrylate)-b-poly(acrylic acid)	Accelerated drug release in an acidic environment	[83]
Nanogel	DDP	Carboxymethyl chitosan, diallyl disulfide, valproate	Reactivate DDP and enhance early apoptosis, and has the ability to improve DDP resistance in NSCLC and enhance anti-tumor efficacy.	[84]

2.1.2.1. Natural polymer-based nanocarriers

Chitosan (Cs) is the second most abundant natural cationic polymer after cellulose with good biocompatibility, low toxicity, low immunogenicity, and biodegradability [85]. The cationic nature of Cs enables it to interact with mucous membranes and exhibit good bioadhesive properties [86]. In vivo studies have found that Cs not only has anti-tumor function itself, but also Cs promote macrophage polarization and activate natural immune responses, thereby improving anti-tumor therapeutic efficacy [87]. In a study that explored whether QUE can reverse the resistance of NSCLC to PTX therapy, targeted biodegradable cetuximab Cs nanoparticles were prepared for PTX and QUE delivery through an ionic cross-linking technology to enhance the anti-tumor activity of PTX and eliminate its toxicity. This drug delivery system not only solves the problem of poor drug solubility but also reduces tumor growth in PTX-resistant xenografts [76]. To overcome acquired drug resistance in epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), Zang et al. synthesized erlotinib-modified chitosan (ECs) by click coupling and developed ECs/indocyanine green self-assembled nanoparticles (GECs) for combined targeted chemo-photodynamic therapy [88]; the GECs produced ROS under NIR laser irradiation and show synergistic molecular targeting and photodynamic therapeutic effects that inhibit NSCLC growth and induce apoptosis. Patients with lung cancer treated with EGFR-TKIs have a 50% chance of uncontrolled disease due to mutations in P.Thr790Met (T790M). A cs-derived nanocarrier DCAFP prepared from α-linolenic acid-modified Cs derivatives and phenylboronic acid-modified Pluronic F127 was designed to induce mitochondrial dysfunction and enhance GFT sensitivity to EGFR^T790M NSCLC [89]. Carboxymethyl chitosan doped with ionic liquids (CMC/ILs) can provide sufficient adsorption groups (-OH, -COOH, and -NH-) and thus increase adsorption capacities of drugs [90]. Novel T7 peptide-modified nanoparticles with CMCS/ILs loaded with DTX and curcumin can inhibit tumor growth by improving the immunosuppressive microenvironment. Although Cs has many benefits, its clinical application is limited by its large molecular weight, poor buffering capacity, solubility only in acidic solutions, and strong intramolecular and intermolecular hydrogen bonds [91]. Huang et al. designed an alkylamine-Cs complex that enhanced the caching ability, promoted lysosomal escape, overcame the intracellular barrier, optimized the shortcomings of Cs, and provided possibilities for the clinical application of Cs [92].

HA is a naturally occurring polysaccharide found in the human body [93]. HA plays a key role in drug delivery due to its multiple properties, including biodegradability, biocompatibility, multiple opportunities for chemical modification, and inherent targeting properties [94]. The repetitive sequence of HA provides multiple binding sites for CD44 sites and facilitate CD44 aggregation, and the binding of HA to CD44 can regulate the growth and proliferation of lung cancer cells [95]. Nanoparticles coupled with HA, the targeting ligand of CD44, can achieve specific recognition of tumor cells and improve the delivery efficiency of anti-tumor drugs [96]. Chemotherapy and photothermal therapy are combined for tumor treatment. HA is modified on the surface of molybdenum disulfide nanosheets as tumor-targeting chemotherapeutic drug nanocarriers for near-infrared photothermal triggered drug release. This HA-rich binding system can selectively target and kill CD44-positive lung cancer cells, especially drug-resistant cells (A549 and H1975). The combined therapy has better synergistic therapeutic effects than chemotherapy or photothermal therapy alone and is expected to be an effective vehicle for tumor-targeted drug delivery. Poly(amide-amine) is an ideal vector for high transfection efficiency. Owing to the presence of terminal amino groups, poly(amide-amine) molecules are positively charged at physiological pH environments and can interact with negatively charged phosphate groups on RNA. The siRNA is mixed with the positively charged poly(amide-amine) and then coated with diselenium-bond-modified HA to shield the excess positive charge. Diselenium-bond-modified HA not only improves the stability and safety of nanoparticles in vivo but also enhances the intracellular behavior of siRNA through redox dual sensitivity, providing a potential pathway for siRNA delivery [97].

Cyclodextrin (CD), a polyhydroxy carbohydrate, is one of the natural materials used in preparing nanocarriers and has the advantages of water solubility, nontoxicity, biodegradability, biocompatibility, and non-carcinogenicity [98]. CD can form inclusion complexes with hydrophobic drugs to improve drug stability and solubility and facilitate drug transport through physiological barriers and biofilms, thus enhancing drug absorption [99,100]. In addition, the supramolecular affinity of CD for drugs can prolong bioavailability, making it an attractive component for controlled-release formulations [101]. Zheng et al. prepared 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD)-modified PTX poly(propylene-co-ethyleneglyceride) nanoparticles by a modified emulsification method using the supramolecular effect of 2-HP-β-CD to improve the bio-transport efficiency of the nanoparticles [77]. The 2-HP-β-CD-modified nanoparticles showed small particle size, high encapsulation rate, and high stability. Compared with unmodified liposomes, HP-β-CD modified nanoparticles exhibited higher cytotoxicity and improved cellular uptake efficiency, with AUC values 2.4 times that of commercially available PTX and 1.7 times that of common PTX poly(propylene-co-ethyleneglycolate) nanoparticles. Thus, the 2-HP-β-CD-modified nanoparticles are potential PTX tumor-targeting agents.

In addition to nanoformulations based on one natural polymer, there are also nanoformulations based on a combination of two natural polymers. The alginate-Cs polyelectrolyte complex (PEC), formed by ionic interactions between the carboxyl group of alginate and amino group of Cs, is an excellent candidate carrier for drug delivery. PEC not only protects a loaded drug while slowing its release but also increases drug uptake through a tight connection with the paracellular transport pathway [102]. PEC encapsulated with bitter amygdalin (Am-PEC) is stable and has a drug encapsulation rate of about 90%. Am-PEC exhibits a significant rate of dissolution in neutral and weakly acidic environments, has a drug release duration of 10 h, and shows a stronger anti-tumor effect than free Am on H1299 cell lines [103].

Although natural polymers are biocompatible, bioactive, degradable, appropriately viscoelastic and easy to process, they also have some limitations, such as poor targeting, high price and low drug blood circulation time. Therefore, scientists have investigated other types of polymer-based nanocarriers to improve the deficiencies of natural polymer-based nanocarriers.

2.1.2.2. Synthetic polymer-based nanocarriers

Copolymers are formed when two or more different types of monomers are joined in the same polymer chain, combining the properties of the monomers. Liposomes have excellent pharmacokinetic properties, high drug loading capacity, polymer-based nanocarriers show sustained release properties and high potential for cellular internalization. The combination of lipids and polymers can improve the limitations of natural polymers such as poor targeting and poor drug blood circulation time. Lipid polymer hybrid nanoparticles (LPHNs) have attracted considerable interest as promising drug delivery systems and novel therapeutic nanocarrier that integrate the advantages of liposomes and polymeric nanoparticles. LPHNs loaded with gemcitabine hydrochloride (GEM) prepared by an improved compound emulsion solvent evaporation method have long cycle times. The GEM in the LPHN formulation has a significantly shorter half-life (4.2-fold) than commercially available natural GEM products, significantly improving the anti-NSCLC efficacy of drugs [104]. To overcome DDP resistance, hybrid nanocarriers (HNCs) containing lipid and poly (lactic acid-polyethylene glycol) di-block copolymer (PEG-PLA) were prepared to enable the simultaneous delivery of DDP octanoate and ABCC3-siRNA to cancer cells. Drug-loaded HNC showed significantly increased cytotoxicity in A549 cell lines and significantly increased drug half-life. siRNA co-loaded agents can reduce DDP resistance and improve efficacy and are novel targets for current DDP-based NSCLC therapy [78]. To optimize the transcription of DNA in the nucleus or the translation of mRNA in the cytoplasmic lysis, Kaczmarek et al. synthesized poly (β amino ester) terpolymers (PBAEs) with modular changes to monomer chemistry to investigate effects on nucleic acid delivery [79]; the results revealed that different nucleic acid molecules require different customized delivery vehicles and PBAE has potential as an intracellular delivery material.

2.1.2.3. Polymeric micelles

Polymeric micelles are self-assembled nanocarriers formed by amphiphilic block polymers. Hydrophilic and hydrophobic blocks forming the crown and core of the micelles, respectively, which can be effectively used to load a variety of anti-cancer drugs and avoid clearance from drug circulation [105]. Polymeric micelles can provide a hydrophobic cavity to encapsulate insoluble drugs and thus facilitate solubilization; drugs encapsulated within polymeric micelles are protected from chemical inactivation and enzymatic degradation [106]. Polymeric micelles that are 10–100 nm in size and have long circulation properties can accumulate at tumor sites through enhanced permeability and retention effects, enhancing anti-cancer activity with few side effects [107]. Liposome-coated polymeric micelles (CoNP-lips) designed for NSCLC treatment using vincristine and DDP as target drugs can accumulate drugs within tumors through enhanced permeability and retention effects. Vincristine and DDP are sustainably released from CoNP-lips and exhibit synergistic anti-tumor effects in C57BL/6 tumor-bearing mice, thus showing potential as agents for the targeted treatment of NSCLC [108].

Conventional polymeric micelles have low stability in vivo and dissociate into polymeric single chains when they enter the bloodstream, resulting in premature drug release, loss of targeting, and low drug efficacy. For this reason, scientists have improved the traditional polymer micelles. Cross-linking of the micelle can effectively prevent the shell-core structure from decomposing prematurely. Guo et al. designed a CD44-targeted GEM nanotherapy, which treats CD44 overexpressed NSCLC by encapsulating hydrophobic phosphorylated gemcitabine prodrug into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG exhibits anti-degradation stability, enhanced internalization and inhibition to CD44⁺ cells, and improved efficacy in the treatment of lung cancer [109]. Polymeric micelles with cross-linked structures not only improve their structural stability, but also maintain their stimulus responsiveness. Sang et al. designed a pH and redox dual stimuli-responsive core-crosslinked polymeric micelles that can load DOX into the core of micelles via hydrophobic and electrostatic interactions. The results show that cross-linked DOX micelles show controlled drug release and are effective in overcoming the premature appearance of drugs outside the cell membrane [110]. In summary, the improved stimulus responsive cross-linked micelles have the characteristics of high drug loading capacity, excellent stability, long-circulation time, minimal drug leakage and high tolerability, making them potential drug-controlled release systems [81].

2.1.2.4. Polymersomes

Polymersomes are a promising drug delivery system that is easy to fabricate, can circulate long, and can significantly improve the accumulation of anti-cancer drugs within tumors [111]. Promotes selective uptake by cancer cells and enhances anti-tumor activity by modifying polymersomes [112]. Yang et al. designed lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs), with small hydrodynamic diameter (60 nm), high pemetrexed disodium (PEM) loading (14.2 wt%), and fast reduction-responsivity and high H460 tumor cell specificity. PEM-loaded CC9-RCPs maintained a long circulation time in H460-bearing nude mice, significantly improving tumor aggregation and tumor penetration with significant efficacy [113]. Yang et al. prepared selective cell penetrating peptide (RLWMRWYSPRTRAYGC)-functionalized polymersomes (SCPP-PS) loaded with methotrexate disodium (MTX), which are is readily fabricated from poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) asymmetric triblock copolymer and RLWMRWYSPRTRAYGC peptide-functionalized PEGP(TMC-DTC) (SCPP-PEG-P(TMC-DTC)) diblock copolymer. Compared with the control, MTX-SCPP-PS showed potent anti-tumor activity, depth of tumor penetration, complete tumor suppression, and significantly improved survival time [82]. Ling et al. designed a novel anisamide-decorated pH-sensitive degradable chimaeric polymersomes (Anis-CPs), which could effectively and targetably deliver apoptotic protein granzyme B (GRB) to lung cancer cells. Ling et al. designed a novel benzamide-modified pH-sensitive degradable chimeric multimer (ANIS-CPS), which could effectively and targetably deliver apoptotic protein granzyme B (GRB) to lung cancer cells. Under moderately acidic conditions, hydrolysis of the acetal bond in poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate resulted in accelerated release of GRB from ANIS-CPS and enhanced anti-tumor efficacy [83].

2.1.2.5. Nanogel

Nanogels are three-dimensional structures formed by networks of chemically or physically cross-linked polymers with hydrophilic or amphiphilic macromolecular chains that can swell by holding large amounts of water while maintaining structural integrity [114]. The swelling, flexibility, modifiability, and low toxicity of nanogels allow encapsulated drugs to be immune to in vivo degradation and elimination and ensure controlled and triggered response at target sites [115]. Faraji et al. found that pH-sensitive HA nanogels showed significant killing effect on A549 and HEK293 cells and had few side effects [116]. Shim et al. prepared a novel Cs dipeptide hydrogel exhibiting efficient controlled release of DOX and exerting significant cytotoxic effects on A549 cells [117]. The valproic acid nanogel prepared by Sun reactivated DDP, enhanced early apoptosis, effectively capped DDP resistance in NSCLC, and enhanced anti-tumor efficacy [84]. In recent years, synthetic hydrogels that have high water absorption capacity, long service lives, and high gel strength have gradually replaced natural hydrogels. Synthetic hydrogels usually have well-defined structures that can be modified to produce customizable degradability and functionality as promising nanodelivery systems. In contrast to the superior pharmacokinetic properties and ease of surface modification of liposomes, polymers have sustained release properties and higher potential for cellular internalization.

2.2. Inorganic framework for lung cancer treatment

Compared with organic nanoparticles, inorganic nanoparticles are used in preparing drug delivery systems because of their naturally high specific surface areas and unique magnetic, optical, and electrical properties. They can significantly improve therapeutic efficacy through targeted ligands while minimizing off-target side effects through drug adsorption and permeation.

2.2.1. Silicon dioxide

Silicon dioxide nanoparticles are used in the biomedical field because of their excellent biocompatibility, drug-gene co-delivery, and customizable physicochemical properties (Figure 3) [118]. Reczyńska et al. prepared superparamagnetic iron oxide nanoparticles modified with silica layers, which significantly reduced iron release by one-tenth of the iron release from unmodified superparamagnetic iron oxide nanoparticles [119]. Mesoporous silica nanoparticles (MSNs) have high porosity with specific surface area up to 1000 m²/g and pore volume of 0.5–3 cm³/g, which are favorable for molecular adsorption. MSN loaded with resveratrol has significant anti-cancer effects in NSCLC [120]. Zhang et al. designed an MSN loaded with DDP and oleanolic acid (OA) and treated A549/DDP cells with apoptosis of up to 15.6%, much higher than free OA (1.8%,) and free DDP (7.6%), which can significantly improve the DDP drug resistance [121]. Rong et al. designed a histone H2A-peptide hybrid upconversion MSN, which has low cytotoxicity, low hemolytic activity, high gene transfection rate, high gene loading, and upconversion imaging [122]. It is expected to be an ideal gene/drug co-vector in clinical tumor therapy. Macrophages can act as ‘scavengers,’ entering the bloodstream to capture foreign invaders, including nanoscale materials. Mesoporous silica nanoparticles can transfer directly between macrophages and heterotypes of A549 lung cancer cells, function as nanomaterials from immune cells to cancer cells, facilitate a synergistic immune response, and are potential drug delivery modality for combined immunization and chemotherapy [123].

Figure 3. Inorganic rice granule formulations with different functional coatings.

2.2.2. Hydroxyapatite

Hydroxyapatite (HAP) nanoparticles are biocompatible calcium phosphate nanomaterials that can target tumor cell mitochondria, have drug-carrying properties based on adsorption mechanisms, and are easy to prepare and modify [124–126]. HAP has a high affinity for DNA, proteins, chemotherapeutic drugs, and antigenic agents. HAP carriers have low systemic toxicity and high affinity for DNA, proteins, chemotherapeutic agents, and antigenic agents. Tseng et al. designed HAP carriers loaded with 5FU (HAP-5FU), and in vitro studies showed that HAP-5FU particles can be intracellularly disassembled and induce cancer cell death effectively [127]. Li et al. developed a bovine serum albumin (BSA)-embedded HAP nanoparticle with high stability, high biocompatibility, and good DOX loading capacity [128]. BSA/HAP has better in vivo tumor targeting than HAP nanoparticles and more significant anti-lung cancer effects. In addition to being a carrier for anti-cancer drugs, HAP selectively kills cancer cells [129]. Sun et al. studied the specific anti-cancer effect of HAP nanoparticles on A549 cells and its mechanism by using human normal bronchial epithelial cells (16HBE) as a control [130]. The results revealed that HAP nanoparticles selectively inhibited the proliferation of cancer cells without any further functionalization and drug loading. In a nude mouse lung cancer A549 cell transplantation model, HAPN treatment showed nearly 40% tumor growth inhibition and had no significant side effects.

2.2.3. Carbon-based nanocarriers

Carbon-based nanomaterials have good stability and unique photothermal conversion efficiency and are often used as drug delivery platforms for tumor therapy, especially for low-dimensional nanocarbon isomers [131,132]. Graphene oxide (GO) shows great potential as a two-dimensional carbon material for drug delivery and cancer therapy [133]. The biomedical toxicity of GO depends mainly on the size of its lamellae, and GO nanosheets prepared from well-stacked graphite nanofibers with a substrate of 50 × 50 nm² not only serve as drug carriers but also significantly enhance the anti-cancer effect of DDP on A549 cells [134]. Zhao et al. developed functional GO nanomaterials with well-defined dimensions and uniform distribution as drug delivery nanosystems for cancer therapy through the redox radical polymerization of PEG-modified GO and cross-linking with cysteine [135]; the cross-linked nanocarriers had significant cytocompatibility, and DOX-loaded nanocarriers had significant killing ability against cancer cells. Photodynamic therapy (PDT) has drawn the attention of researchers because of its minimal invasiveness and side effects. Nitrogen doping patches vacancy defects in GO surfaces and enhances orbital conjugation on dots, thereby inhibiting the formation of photogenerated charge complex. Shih et al. synthesized nitrogen-doped graphene oxide dots (NGODs) as a highly biocompatible photosensitizer for PDT [136]. In the presence of ascorbic acid, NGODs are taken up into cells to produce concentrated H₂O₂, which effectively kills lung cancer cells and is highly safe for normal cells. In addition, GO can be used as a sensitizer to increase the sensitivity of cancer cells to chemotherapeutic drugs and can be assembled through metal ion induction for the construction of an electronic nose for exhaled breath diagnosis of lung cancer, accurately distinguishing between healthy groups and patients with lung cancer [137,138]. These results suggested that GO is malleable and has great potential as a material for lung cancer treatment, noninvasive disease screening, and personalized medical management.

Compared with GO, reduced graphene oxide (rGO) has lower cytotoxicity and stronger photothermal conversion and is widely used in biomedical research [139]. Multifunctional nanocarrier development for cancer treatment is urgently needed. rGO loaded with PTX can significantly reduce the survival of A549 cells by reducing GO to rGO through an efficient reduction method. Silver-doped highly reduced GO nanocomposites synthesized by Khan using a green method can block the A549 cell cycle in the G0/G1 phase and induce A549 cell apoptosis [140]; the nanocomposites showed potential as a targeted chemotherapeutic agent for lung cancer. However, the toxicity of the efficient reducing agent itself is uncontrollable, and to prevent the high toxicity brought by reducing agents, rGO was prepared using ascorbic acid as a green reducing agent and loaded with GEM; the prepared GEM-rGO nanoparticles were used in anti-NSCLC studies. The results showed that GEM-rGO significantly enhanced the therapeutic effect of NSCLC in vitro and in vivo in combination with chemotherapy and photothermal therapy and is a promising candidate for the treatment of lung cancer [141].

Multiwalled carbon nanotubes have been developed as a novel drug delivery system for tumor therapy due to their small diameter, internal hollow, high drug encapsulation capacity, neutral electrostatic potential, high cell penetration capacity, and cancer cell targeting [142]. Singh et al. fabricated a Cs-FA conjugated multiwalled carbon nanotube that can be internalized into lung cancer cells via the FR-mediated endocytic pathway [143]; the effectiveness of the nanotube for human lung cancer cells (A549 cells) was 89 times that of the DTX formulation. Mesoporous carbon nanoparticles are excellent options for drug delivery due to their well-defined mesoporous channels, large surface areas, and the natural properties of their carbonaceous composition [144]. Tian et al. prepared a novel yolk-shell Fe₃O₄@mesoporous carbon nanoparticle, which resulted in sufficient mesoporous carbon nanoparticle cell internalization [145]. Under the synergistic effect of chemotherapy and phototherapy, this nanoparticle exhibited significant tumor cell ablation in vitro and in vivo under 808 nm NIR laser irradiation.

2.2.4. Other materials

In addition to the aforementioned nanoparticles, some other metal oxide nanoparticles (ZnO and CuO) can induce apoptosis in cancer cells and show potential as materials for drug delivery and tumor imaging applications [146]. ZnO nanoparticles have preferential photocatalytic properties in UV light and can be used to kill cancer. To increase the amount radiation absorbed by ZnO nanoparticles and enhance their imaging visualization capabilities, gadolinium (Gd) was selected as a high atomic number element doped into the structure of ZnO nanoparticles in the preparation of Gd-doped ZnO nanoparticles. The nanoparticles produced high cytotoxicity and genotoxicity to irradiated lung cancer cells at megavoltage radiation energy and enhanced the contrast of CT and MR images of cancer cells, contributing to the further development of this effective therapeutic diagnostic platform for clinical applications [147]. Hira et al. developed a pectin-guar gum-zinc oxide nanocomposite (PEC-GG-ZnO) as an immunomodulator to enhance the ability of human peripheral blood lymphocytes to kill cancer cells [148]. The results showed that PEC-GG-ZnO pretreated human peripheral blood lymphocytes showed enhanced cytotoxicity against A549 cells compared with untreated human peripheral blood lymphocytes. This novel nanocomposite can be used as a promising cancer therapeutic and immunomodulatory agent. CuO nanoparticles synthesized by chemical methods are unsuitable for biological applications due to their inability to prevent the adsorption of toxic chemicals during the synthesis process. Wu et al. developed a hybrid delivery system for green synthesized CuO nanoparticle aptamer coupling using Coleus aromaticus leaf extract as raw material [149]. This delivery system effectively delivered miRNA to lung cancer cells, thus serving as an effective platform for intracellular miRNA delivery and improving the therapeutic outcome of lung cancer. Reczyńska et al. developed a novel stimulus-sensitive drug carrier by combining superparamagnetic iron oxide nanoparticles with solid lipid particles [150].

A drug delivery vehicle and a particle (MP) composed of PTX is delivered to a patient by inhalation using a standard DPI, and an external magnetic field guides the MP to the tumor site. Once the MP accumulates in the tumor, an alternating electromagnetic field is applied to heat the nanoparticles embedded in the particles to approximately 42–47°C, causing the fatty acid matrix of the nanoparticles to melt, releasing PTX to the tumor, enhancing bioavailability, and increasing cytotoxicity. After the fatty acids are metabolized in the surrounding cells, the remaining nanocarriers will be removed from the lungs through natural clearance mechanisms. By modifying the nanoparticles, the efficacy of the developed drug carriers can be further improved, and this improvement will greatly enhance the effectiveness of anti-cancer treatment, which is a chance of recovery for many lung cancer patients.

3. Conclusion and future directives

The American Cancer Annual Report projects that in 2023, lung cancer will remain the leading cause of cancer deaths, causing an average of 350 deaths per day [1]. The search for novel treatments to improve the cure rate of lung cancer is imminent.

Nanotechnology-based precision targeted therapy for lung cancer aims to minimize the toxic effects of drugs and enhance the efficacy of anti-lung cancer chemotherapeutic agents and better tumor imaging. In recent years, this area of research has been greatly expanded and is being used to improve patients’ quality of life and overall survival rates. This paper introduces nanotechnology-based targeted lung cancer therapies in recent years, revealing the importance of nanotechnology in lung cancer diagnosis and treatment, with a view to providing researchers with ideas for developing new anti-lung cancer drugs and promoting the development of nanotechnology-based targeted lung cancer therapies. LIANG et al. constructed a nanocomplex modified with tumor cell membranes (M@MTCA) for the targeted delivery of DDP and PD-L1 nucleic acid aptamer (APT) [151]. M@MTCA induced ICD in tumor cells, and converted low-immunogenic M@MTCA induced ICD in tumor cells, converted ‘cold’ tumors to ‘hot’ tumors with high immunogenicity, and synergized with APT to provide a potent anti-tumor immune response, providing an ideal combination therapy strategy for conventional chemo-immunotherapy.

Currently, researchers are exploring alternative therapies, such as targeted therapy, thermotherapy, and photodynamic therapy, in addition to nanoparticle therapy to improve the efficiency of tumor ablation, and all of these therapies require appropriate biologically based materials for modification. Liposomes, polymers, and inorganic nanoparticles are all good biologic materials, and they have distinct characteristics. No biomaterial is ideal by itself; they all have advantages and disadvantages, and how to amplify the advantages and circumvent the disadvantages is what we are looking into.

4. Expert opinion

Lung cancer is a major public health problem worldwide and is one of the types of cancer with the highest morbidity and mortality rates. Current treatment modalities for lung cancer have limitations, and the nonspecific nature of potent chemotherapeutic agents often leads to significant side effects. Therefore, exploring a more effective treatment modality that improves therapeutic efficacy while mitigating side effects is now an urgent requirement. Nanoparticles with multiple functions are designed to overcome the various limitations of drugs and conventional drug delivery systems. Engineered nanoparticles that specifically target cancer cells can reduce collateral damage to normal tissues due to the pan-toxic effects of drugs. Nanoparticles can provide sufficient space and protection for drug molecules, which can protect the integrity of the drug during transport in the circulation and prevent the drug from contacting normal non-targeted tissues. This mode of drug delivery with superior pharmacokinetic properties in the in vivo circulation enhances the half-life of the drug and provides tissue-targeted selectivity and the ability to overcome biological barriers has brought a revolution in the field of oncology. Nanoparticles have been used for the treatment of lung cancer, but they have not yet been introduced into the clinic in large quantities because they may still have safety concerns.

Nanoparticles are not only able to encapsulate drugs with different physicochemical properties, but also make them very effective in passive targeting through enhanced EPR effects. In addition, their surfaces can be functionalized with different targeting components for active targeting to selectively target cancer cells and tumors.

Drug delivery using nanoparticles for the treatment of lung cancer involves pulmonary routes of drug delivery in addition to the intravenous delivery described in the article. Inhaled anti-cancer therapy with nanocarriers is an exciting and growing area of research, and it is a promising treatment strategy. The use of inhaled nanocarriers offers many advantages over conventional lung cancer treatments, especially for patients with lung cancer that cannot be surgically removed. Pharmacokinetically, inhalation delivers chemotherapeutic drugs to target cancer cells, avoiding hepatic metabolism. Inhalable Pirfenidone cationic liposomes can target chemotherapeutic drugs deep into the tumor and help the drug accumulate at the target site, thus reducing systemic toxicity [45]. Compared to inhaled paclitaxel-based preparations, Folic acid graft copolymer of paclitaxel-loaded surface-modified solid lipid nanoparticles (SLNS) with polyethylene glycol chitosan significantly prolonged in vivo exposure time to 6 h (in female CD-1 and BALB/c mice) and limited systemic distribution of the drug after pulmonary delivery [152]. However, the absorption, pulmonary clearance mechanisms, biodistribution and tumor penetration of inhaled drug-carrying particles are influenced by many factors, such as the physicochemical properties of the drug/particles, the characteristics and composition of the formulation used, the histological characteristics of the respiratory system, and the relevant pathological conditions. Further, pulmonary tolerance and the potential risk of local pulmonary toxicity and adverse effects are among the main concerns due to the inherent cytotoxic activity of anti-cancer drugs.

Nano anti-cancer drugs effectively kill tumor cells through five main steps: blood circulation, tumor accumulation, deep penetration, cellular internalization and drug release. Any hindrance in this process will affect the overall therapeutic effect of the drug. Therefore, how to optimize nanocarriers to improve the therapeutic efficacy while ensuring their structural stability is the focus of the current research to be conducted. In conclusion, we strongly believe that both intravenous input nanoparticles and pulmonary inhalation nanoparticles hold great promise for loading anticancer drugs for the treatment of lung cancer. In the next five or ten years, nano-formulations will continue to be the hot spot of research, and the current problems will be gradually optimized. Nano-anti-cancer agents will be as widely used in clinical treatment as chemotherapeutic drugs.

Article highlights

• Lung cancer is a major public health problem worldwide. However, current treatment options are limited, lung cancer mortality remains at the top of the list of malignancies, and most chemotherapeutic agents are associated with some adverse effects.

• Nanodelivery systems have significant potential to improve the efficacy of lung cancer treatment and reduce the toxic side effects of chemotherapeutic agents.

• Active targeting and passive targeting of nanoparticles for drug delivery enhances the efficacy, reduces the disadvantages of off-targeting, and creates conditions to ensure effective lung delivery as well as to overcome the biological barriers in the lung.

• Nanoparticles can provide sufficient space and protection for drug molecules, which can protect the integrity of the drug during transport in circulation and prevent contact with normal non-targeted tissues.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript is supported by the Shanghai Science and Technology Plan Project [23YF1447800]，the Shanghai Natural Science Foundation Project [23ZR1463900], the Shanghai science and technology commission scientific research project [21Y11922400], the Health Commission of Shanghai [20214Y0377], National Dragon Medical Practitioner Nursery Program of Longhua Hospital, Shanghai University of Traditional Chinese Medicine [PY2022012], Dragon Medical Science and Technology Innovation Incubation Program [zyzk001-05] and the clinical science and technology innovation cultivation projects of Longhua Hospital [PY2022002].