Application of nanomaterials in precision treatment of lung cancer

Summary

Lung cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by high mortality rates due to its aggressive nature, metastatic potential, and drug resistance. Despite advancements in conventional therapies, their efficacy is often limited by systemic toxicity, poor tumor specificity, and the emergence of resistance mechanisms. Nanomedicine has emerged as a promising approach to address these challenges, leveraging the unique physicochemical properties of nanomaterials to enhance drug delivery, reduce off-target effects, and enable combination therapies. This review provides a comprehensive overview of the applications of nanomaterials in lung cancer treatment, focusing on advancements in chemotherapy, phototherapy, and immunotherapy. Key strategies include the development of stimuli-responsive nanoparticles, active targeting mechanisms, and multifunctional platforms for co-delivery of therapeutic agents. Notable successes, such as liposomal formulations and polymeric nanoparticles, highlight the potential to overcome biological barriers and improve therapeutic outcomes. However, significant challenges remain, including limited tumor penetration, immunogenicity, scalability in manufacturing, and regulatory complexities. Addressing these limitations through innovative design, advanced manufacturing technologies, and interdisciplinary collaboration will be critical to translating nanomedicine from bench to bedside. Overall, nanomedicine represents a transformative frontier in lung cancer therapy, offering the potential to improve patient outcomes and quality of life.

Health sciences; Natural sciences; Applied sciences

Introduction

Lung cancer stands as one of the most prevalent and lethal malignancies worldwide, with an estimated 2 million new cases and 1.76 million deaths annually. Despite significant advances in our understanding of cancer biology, the development of predictive biomarkers, and refinements in treatment strategies over the past two decades, lung cancer continues to pose significant challenges to clinicians and researchers alike.^1,2,3

The aggressive nature of lung cancer, particularly in its advanced stages, is characterized by rapid metastatic spread, often resulting in multi-organ dysfunction. This metastatic propensity, coupled with the development of drug resistance, remains the primary cause of mortality in lung cancer patients. Current therapeutic approaches, while improving, still fall short in effectively managing advanced disease.^4,5,6

Conventional chemotherapy, a mainstay in lung cancer treatment, operates on the principle of targeting rapidly dividing cells. However, this approach is inherently non-specific, leading to collateral damage to healthy tissues and a plethora of adverse effects. These side effects often necessitate dose reductions or treatment discontinuations, compromising therapeutic efficacy. Moreover, the emergence of drug resistance further limits the long-term effectiveness of chemotherapy.^7,8

In light of these challenges, the field of nanomedicine has emerged as a promising avenue for enhancing cancer therapy. Nanomaterials, typically defined as materials with dimensions between 1 and 100 nm, offer unique physicochemical properties that can be harnessed for therapeutic applications. The potential of nanomaterials in cancer treatment was first realized with the U.S. Food and Drug Administration (FDA) approval of Doxil, a liposomal formulation of doxorubicin, in 1995. Since then, there has been an explosion of research into various nanoplatforms for cancer therapy.⁹

Nanoparticles present several advantages over conventional drug formulations. They can enhance therapeutic efficacy through multiple mechanisms as follows.¹⁰ (1) Increased bioavailability: nanoformulations can improve the solubility and stability of poorly water-soluble drugs, enhancing their bioavailability. (2) Prolonged circulation times: surface modifications, such as PEGylation, can shield nanoparticles from rapid clearance by the reticuloendothelial system, extending their circulation half-life. (3) Reduced non-specific toxicity: by encapsulating cytotoxic agents within nanocarriers, systemic exposure can be minimized, potentially reducing off-target effects. (4) Cell-specific targeting: nanoparticles can be functionalized with ligands that specifically bind to receptors overexpressed on cancer cells, enhancing selective drug delivery. (5) Overcoming biological barriers: certain nanoformulations can facilitate the crossing of biological barriers, such as the blood-brain barrier, expanding the reach of therapeutic agents.⁹

In the context of lung cancer, nanomaterials offer particular promise due to the unique anatomical and physiological characteristics of the lung. The vast surface area and extensive vasculature of the lungs provide opportunities for both systemic and inhalational delivery of nanoparticle-based therapies. Additionally, the leaky vasculature often associated with lung tumors can be exploited through the enhanced permeability and retention (EPR) effect, allowing passive accumulation of nanoparticles at tumor sites.^11,12

This review aims to provide a comprehensive overview of the application of nanomaterials in lung cancer treatment, with a focus on recent advancements in both chemotherapy and immunotherapy. We will explore the diverse types of nanomaterials being investigated, their mechanisms of action, and their potential to overcome current limitations in lung cancer therapy. Furthermore, we will critically examine the challenges and limitations associated with nanomaterial-based approaches, including issues of biocompatibility, manufacturing scalability, and regulatory considerations.

Nanomaterials for chemotherapy in lung cancer

Drug delivery: enhancing specificity and efficacy

The application of nanomaterials in lung cancer chemotherapy represents a paradigm shift in drug delivery strategies. Conventional chemotherapeutic agents, while potent against cancer cells, often lack specificity, leading to significant off-target effects and dose-limiting toxicities. Nanomaterials offer a sophisticated solution to this long-standing challenge by providing a versatile platform for targeted drug delivery.

The fundamental principle underlying nanoparticle-mediated drug delivery is the ability to encapsulate or conjugate chemotherapeutic agents within nanocarriers. This approach offers several advantages.^13,14,15

• (1)Protection of the drug: encapsulation shields the drug from degradation in the biological milieu, potentially enhancing its stability and half-life.
• (2)Controlled release: nanocarriers can be designed to release their payload in response to specific stimuli (e.g., pH, temperature, or enzymatic activity), allowing for precise control over drug release kinetics.
• (3)Enhanced permeability and retention (EPR) effect: nanoparticles can passively accumulate in tumor tissues due to their leaky vasculature and impaired lymphatic drainage, a phenomenon known as the EPR effect.
• (4)Active targeting: surface functionalization with ligands specific to tumor-associated antigens can further enhance the selectivity of nanoparticle accumulation in cancer cells.

Recent advances in nanotechnology have led to the development of a diverse array of nanocarriers for lung cancer chemotherapy. These include liposomes, polymeric nanoparticles, dendrimers, and inorganic nanoparticles, each with unique properties that can be tailored for specific applications.¹⁵

Liposomes, for instance, have shown particular promise in the delivery of hydrophobic drugs. A study by Merve Karpuz et al. demonstrated that liposomal formulation of paclitaxel significantly enhanced its accumulation in lung tumor tissue compared to free paclitaxel, resulting in improved anti-tumor efficacy and reduced systemic toxicity in a murine model of non-small cell lung cancer (NSCLC).¹⁶

Polymeric nanoparticles offer another versatile platform for drug delivery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, for example, have been extensively studied due to their biodegradability and biocompatibility. A recent investigation by Hong et al. showcased the potential of PLGA nanoparticles for co-delivery of cisplatin and curcumin in lung cancer therapy.¹⁷ The dual-drug loaded nanoparticles demonstrated synergistic anti-tumor effects and overcame cisplatin resistance in both in vitro and in vivo models of NSCLC.¹⁷

Inorganic nanoparticles, such as mesoporous silica nanoparticles (MSNs), have gained attention due to their high drug loading capacity and potential for stimuli-responsive drug release. Some researchers developed pH-responsive MSNs for the delivery of doxorubicin to lung cancer cells.^18,19,20 The nanoparticles exhibited minimal drug release at physiological pH but rapidly released their payload in the acidic tumor microenvironment, leading to enhanced therapeutic efficacy and reduced cardiotoxicity compared to free doxorubicin.

The size and surface characteristics of nanoparticles play a crucial role in determining their efficacy as drug delivery vehicles. Particles in the size range of 10–100 nm are generally considered optimal for tumor targeting, as they are large enough to avoid rapid renal clearance but small enough to extravasate through leaky tumor vasculature.^21,22 Surface charge also significantly influences nanoparticle behavior in vivo, with slightly negative or neutral particles typically exhibiting longer circulation times and improved tumor penetration compared to highly charged particles.^23,24

Recent advancements in nanoparticle engineering have led to the development of more sophisticated delivery systems. For instance, hierarchical nanoparticles that can change their size or surface properties in response to tumor-specific stimuli have shown promise in overcoming biological barriers to drug delivery. Multiple studies have focused on developing nanoparticle systems capable of undergoing morphological transformations within the tumor microenvironment to enhance drug penetration and therapeutic efficacy. For example, a dual-component peptide nanoparticle system can transform from large particles (approximately 170 nm) into smaller particles (<30 nm) under the acidic tumor microenvironment and near-infrared (NIR) laser irradiation, thereby improving tumor penetration and cellular internalization.²⁵ Additionally, another nanomaterial achieves morphological transformation in the tumor microenvironment through an enzyme-responsive mechanism, enhancing drug permeability and retention time.²⁶

Another innovative approach involves the use of cell membrane-coated nanoparticles. By coating nanoparticles with membranes derived from cancer cells or immune cells, researchers have created biomimetic delivery systems that can evade immune clearance and achieve enhanced tumor targeting. A study by Zhao et al. demonstrated that neutrophil membrane-coated nanoparticles loaded with paclitaxel exhibited superior lung tumor targeting and anti-metastatic effects compared to uncoated nanoparticles.²⁷

Enhanced treatment: overcoming limitations of conventional chemotherapy

While traditional chemotherapy has been a cornerstone in lung cancer treatment, its efficacy is often limited by poor bioavailability, rapid clearance, and severe side effects. Nanomaterial-based approaches offer innovative solutions to these long-standing challenges, potentially enhancing the therapeutic index of existing chemotherapeutic agents.

Cisplatin, a platinum-based compound, remains one of the most widely used chemotherapeutic agents for both NSCLC and small cell lung cancer (SCLC). However, its clinical utility is hampered by poor water solubility, rapid clearance, and dose-limiting nephrotoxicity. Nanomaterial-based formulations of cisplatin have shown promise in addressing these limitations.^28,29

Multiple studies have shown that pH-responsive nanocarrier systems can remain stable at physiological pH while rapidly releasing drugs in the acidic tumor microenvironment, thereby enhancing drug accumulation in tumors and improving anti-tumor efficacy.^30,31,32,33 For example, pH-responsive cisplatin-loaded liposomes and calcium compound nanoparticles have been developed, demonstrating significant anti-tumor activity and reduced systemic toxicity in both in vitro and in vivo experiments.^30,32,33

Another innovative approach involves the use of “coordination-driven self-assembly” technology to construct cisplatin metal macroring structures with porphyrin. When co-assembled with amphiphilic polypeptides, these structures form stable nanomaterials with enhanced tumor cell uptake and reduced toxicity to normal cells. This strategy not only improves the delivery of cisplatin but also allows for the incorporation of imaging agents, enabling theranostic applications.^34,35

Beyond platinum-based agents, nanomaterials have shown potential in enhancing the efficacy of other chemotherapeutic drugs. Paclitaxel, a widely used taxane, suffers from poor aqueous solubility and systemic toxicity. Albumin-bound paclitaxel nanoparticles (nab-paclitaxel, marketed as Abraxane) have been approved for use in advanced NSCLC, demonstrating improved efficacy and reduced toxicity compared to conventional paclitaxel formulations.^36,37,38

The development of multifunctional nanoparticles capable of delivering multiple therapeutic agents simultaneously represents another promising avenue. Man et al. developed a pH/reactive oxygen species/metalloprotease (pH/ROS/MMP-2) triple-responsive nanoparticle system (PEG-M-PPMT) encapsulating both sorafenib and the photosensitizer Ce6. This system demonstrated remarkable versatility, leveraging the EPR effect for tumor accumulation, MMP-2-mediated size reduction for improved penetration, and pH/ROS-triggered drug release within tumor cells.³⁹

Nanomaterials also offer unique opportunities for combining chemotherapy with other treatment modalities. For instance, the integration of photothermal therapy (PTT) with chemotherapy has shown synergistic effects. Guo et al. developed gold nanorods (GNRs) functionalized with a platinum(IV) prodrug, creating a system capable of both photothermal ablation and chemotherapy. Upon NIR irradiation, these nanoparticles generated localized heat, triggering the release of the active platinum species. This approach demonstrated superior anti-tumor efficacy compared to either modality alone in NSCLC models.⁴⁰

Overcoming drug resistance: nanomaterial-based strategies

Drug resistance remains one of the most formidable challenges in lung cancer treatment, often leading to therapeutic failure and disease progression. Nanomaterials offer innovative approaches to combat drug resistance through various mechanisms, potentially resensitizing resistant tumors to chemotherapy.

Multidrug resistance (MDR) in lung cancer is frequently associated with the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp). These efflux pumps actively expel a wide range of chemotherapeutic agents from cancer cells, reducing their intracellular concentration and efficacy. Nanoparticle-based strategies to overcome MDR can be broadly categorized into three approaches.

• (1)Co-delivery of chemotherapeutic agents and MDR inhibitors^41,42,43: this approach involves simultaneous delivery of a chemotherapeutic drug and an MDR inhibitor, such as verapamil or tariquidar. By encapsulating both agents within a single nanocarrier, their co-localization in cancer cells can be ensured, potentially maximizing the inhibition of drug efflux.
• (2)Nanocarriers that bypass efflux pumps^42,43,44: some nanoparticle formulations can evade recognition by efflux pumps, either due to their size or surface properties. For instance, polymeric micelles have shown promise in this regard. Research by He et al. demonstrated that pluronic block copolymer micelles loaded with paclitaxel could effectively overcome MDR in lung cancer cells. The micelles not only bypassed P-gp-mediated efflux but also sensitized the cells to paclitaxel by depleting intracellular ATP, a crucial cofactor for efflux pump function.⁴⁵
• (3)Targeted delivery of siRNA to suppress MDR-related genes^46,47: RNA interference (RNAi) offers a powerful tool to directly suppress the expression of MDR-related genes. However, the delivery of siRNA to tumor cells in vivo remains challenging due to its rapid degradation and poor cellular uptake. Nanoparticle-mediated delivery of siRNA targeting MDR genes has shown promising results. Several studies have utilized lipid-polymer hybrid nanoparticles for co-delivery of siRNA targeting MDR1 (the gene encoding P-gp) and paclitaxel. This approach achieved significant downregulation of P-gp expression and restored sensitivity to paclitaxel in resistant NSCLC models.^48,49,50,51

Enhanced chemotherapy combined with phototherapy

The integration of chemotherapy with phototherapy represents a promising strategy to enhance therapeutic efficacy in lung cancer treatment. Phototherapy, encompassing both photodynamic therapy (PDT) and PTT, offers several advantages over traditional treatment modalities, including high spatiotemporal selectivity, minimal invasiveness, and the potential to overcome drug resistance mechanisms.⁵²

Nanomaterials play a crucial role in facilitating the combination of chemotherapy and phototherapy by serving as multifunctional platforms that can simultaneously carry chemotherapeutic agents and photosensitizers or photothermal agents. This synergistic approach leverages the unique properties of nanomaterials to overcome limitations of each individual therapy and potentially achieve superior therapeutic outcomes.

PDT combined with chemotherapy

PDT involves the administration of a photosensitizer that, when activated by light of a specific wavelength, generates ROS that induce cytotoxicity. The combination of PDT with chemotherapy offers several potential benefits.

• (1)Enhanced drug delivery: light-triggered release of chemotherapeutic agents from nanocarriers can improve spatial and temporal control over drug delivery.^53,54,55
• (2)Synergistic cytotoxicity: ROS generated by PDT can sensitize cancer cells to chemotherapeutic agents.^56,57,58
• (3)Overcoming drug resistance: PDT can potentially reverse mechanisms of chemoresistance by altering cellular signaling pathways.^57,58,59

A groundbreaking study by Yuanyuan et al. demonstrated the potential of this approach using a photosensitive liposome combining the photosensitizer Ce6 with a platinum prodrug (Pt(IV)).⁶⁰ This nanoplatform, termed Pt/Ce6-LP, exhibited several innovative features: alleviation of tumor hypoxia through modulation of H₂O₂ and Glutathione (GSH) balance, enhancing PDT efficacy; on-demand drug release triggered by light activation of unsaturated phospholipids; reversal of cisplatin resistance in tumor cells; induction of immunogenic cell death (ICD), promoting anti-tumor immune responses; and transformation of tumor-associated macrophages toward an immunostimulatory M1 phenotype. In vivo studies demonstrated superior anti-tumor efficacy of Pt/Ce6-LP compared to individual therapies, highlighting the potential of this approach in overcoming treatment resistance and enhancing therapeutic outcomes.

PTT combined with chemotherapy

PTT utilizes photothermal agents that can convert light energy into heat, inducing localized hyperthermia in tumor tissues. The combination of PTT with chemotherapy offers several advantages.

• (1)Enhanced drug penetration: mild hyperthermia can increase vascular permeability and improve drug delivery to tumors.^61,62
• (2)Synergistic cytotoxicity: hyperthermia can sensitize cancer cells to chemotherapeutic agents.^63,64,65
• (3)Triggered drug release: heat generated by PTT can be used to trigger the release of drugs from thermosensitive nanocarriers.^62,66

Guo et al. developed an innovative nanoplatform combining GNRs with a platinum(IV) prodrug for combined PTT and chemotherapy in lung cancer.⁴⁰ This system, termed GNR@polyPt(IV), was created through in situ polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) and platinum(IV) complex prodrug monomers on the surface of GNRs. Key features of this nanoplatform include: high drug loading capacity and targeted rapid drug release, minimal toxicity to normal cells, significant NIR photothermal effects and tumor accumulation capabilities, and enhanced tumor accumulation through mild hyperthermia. In vivo studies demonstrated that GNR@polyPt(IV) combined with laser irradiation achieved superior anti-tumor efficacy compared to either modality alone, highlighting the synergistic potential of PTT and chemotherapy.

Table 1 offers an overview of diverse nanoparticle carriers and their therapeutic roles in lung cancer treatment. The table highlights specific drug-nanomaterial combinations and their synergistic effects in enhancing treatment outcomes, which is a testament to the versatility of nanomaterials in combination therapies.

Table 1.

Overview of diverse nanoparticle carriers and their therapeutic roles in lung cancer treatment

Drug + Nanomaterials	–	Effect
CA-MNPs+DOX-TSLPs+MΦs	Du V N et al.	CA-MNPs have a magnetic targeting function that produces a photothermal effect under near-infrared light, triggering drug release from TSLPs.
PEG-M-PPMT+sorafenib+Ce6	Man S et al.	High permeability and retention effect aggregates at the tumor site, and laser irradiation of Ce6 can rapidly increase ROS concentration to promote drug cascade release.
GNR@polyPt(IV)	Guo D et al.	Targeted rapid drug release, low toxicity to normal cells, significant near-infrared thermal response and tumor accumulation capacity.
Pt/Ce6-LP	Yuanyuan Y et al.	Reversal of drug resistance and induction of tumor-associated macrophages to immune-activated M1-type.
LT-NPs(VPF、FRRG、DOX)	Jiwoong C et al.	In histone B overexpressing cancer cells, LT-NPs are specifically cleaved to produce VPF and DOX, inducing immunogenic cell death (ICD). It highly accumulates in tumors and induces enhanced antigen presentation by DC cells and significantly inhibits tumor growth, recurrence, and lung metastasis in combination with PD-L1 inhibitors.
SSIL2(peg-bisphospholipid derivatives)	Elena et al.	Antigen-bound counterpart of trastuzumab fragments, firmly anchored to the liposome surface and correctly directed outward to the targeting fraction.
GO	Ghorban iet al	Adsorption of F-actin disrupts the structure of the cytoskeleton, which in turn activates the host anti-tumor immune response and affects the growth and metastasis of A549 cells.

The table highlights the specific drug-nanomaterial combinations, such as CA-MNPs with DOX-TSLPs and macrophages for magnetic targeting and photothermal effects, and PEG-M-PPMT with sorafenib and Ce6 for enhanced permeability and reactive oxygen species-mediated drug release. Other entries include GNR@polyPt(IV) for targeted drug delivery and photothermal therapy, Pt/Ce6-LP for reversing drug resistance, and LT-NPs for inducing immunogenic cell death. Additionally, SSIL2 utilizes trastuzumab for precise targeting, and GO disrupts cytoskeletal structures to activate immune responses.

Immunotherapy of nanomaterials in lung cancer

Immunotherapy has emerged as a revolutionary approach in lung cancer treatment, offering the potential for durable responses and improved long-term survival. However, the efficacy of current immunotherapeutic strategies is limited by factors such as low response rates, immune-related adverse events, and the development of resistance mechanisms. Nanomaterials offer innovative solutions to enhance the delivery, efficacy, and safety of cancer immunotherapies.

Organic nanomaterials

Organic nanomaterials, including polymeric nanoparticles, liposomes, and lipid nanoparticles (LNPs), have gained significant attention in cancer immunotherapy due to their biocompatibility, biodegradability, and versatility in design and functionalization.

Polymeric nanomaterials

Polymeric nanoparticles offer several advantages for cancer immunotherapy, including the following: tunable physicochemical properties, high drug loading capacity, controlled release kinetics, and potential for surface modification to enhance targeting and cellular uptake.

Recent advancements in polymeric nanoparticles for lung cancer immunotherapy include the following.

• (1)Delivery of immune checkpoint inhibitors: polymeric nanoparticles have shown promise in enhancing the delivery and efficacy of immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies.^67,68,69 For instance, Zhang et al. developed PEGylated PLGA nanoparticles loaded with an anti-PD-1 antibody. These nanoparticles demonstrated improved tumor accumulation and enhanced anti-tumor efficacy compared to free antibody in a murine model of lung cancer.⁷⁰
• (2)Co-delivery of immunomodulators: polymeric nanoparticles can facilitate the co-delivery of multiple immunomodulatory agents, potentially achieving synergistic effects.^71,72,73
• (3)Nanovaccines: polymeric nanoparticles can serve as effective delivery vehicles for cancer vaccines, enhancing antigen presentation and stimulating robust anti-tumor immune responses.^71,74,75

Liposomes

Liposomes, spherical vesicles composed of phospholipid bilayers, have been extensively studied as drug delivery vehicles in cancer therapy. In the context of lung cancer immunotherapy, liposomes offer several advantages as follows: ability to encapsulate both hydrophilic and hydrophobic molecules, high biocompatibility and biodegradability, flexibility in surface modification for targeted delivery, and potential for stimuli-responsive drug release.

Recent advancements in liposomal formulations for lung cancer immunotherapy include the following.

• (1)Cationic liposomes for nucleic acid delivery^76,77: cationic liposomes have shown promise in delivering immunostimulatory nucleic acids, such as CpG oligonucleotides and siRNA targeting immunosuppressive pathways.
• (2)Stealth immunoliposomes^78,79: PEGylated liposomes functionalized with targeting moieties, known as stealth immunoliposomes, have shown potential in enhancing the delivery of immunotherapeutic agents to lung tumors.
• (3)pH-sensitive liposomes^80,81: liposomes designed to release their cargo in response to the acidic tumor microenvironment have shown promise in enhancing the intracellular delivery of immunotherapeutic agents.
• (4)Thermosensitive liposomes⁸¹: liposomes that release their cargo in response to mild hyperthermia offer the potential for spatiotemporal control over drug delivery in combination with local hyperthermia treatment.

Lipid nanoparticles

LNPs have gained significant attention in recent years, particularly due to their success in mRNA vaccine delivery for COVID-19. In the context of lung cancer immunotherapy, LNPs offer several advantages: high encapsulation efficiency for nucleic acids and hydrophobic drugs, excellent stability and long shelf life, potential for targeted delivery through surface modification, and ability to induce immunostimulatory effects.

Recent developments in LNP-based approaches for lung cancer immunotherapy include the following:

• (1)mRNA vaccines: LNP-formulated mRNA vaccines encoding tumor-associated antigens have shown promise in eliciting robust anti-tumor immune responses.^82,83
• (2)siRNA delivery: LNPs have shown potential in delivering siRNA targeting immunosuppressive pathways in the tumor microenvironment.⁸⁴
• (3)Co-delivery of immunomodulators: LNPs can facilitate the co-delivery of multiple immunomodulatory agents, potentially achieving synergistic effects.
• (4)Hybrid LNP systems: hybrid nanoparticles combining lipids with other materials, such as polymers or inorganic nanoparticles, offer the potential to combine the advantages of different nanoplatforms.^76,83

Inorganic nanomaterials

Inorganic nanomaterials have attracted significant attention in cancer immunotherapy due to their unique physicochemical properties, including high surface-to-volume ratios, tunable size and shape, and distinctive optical and magnetic properties. These materials offer diverse opportunities for enhancing immunotherapeutic approaches in lung cancer treatment.

Gold nanoparticles

Gold nanoparticles (AuNPs) have emerged as versatile platforms for cancer immunotherapy due to their biocompatibility, ease of surface functionalization, and unique optical properties. In the context of lung cancer immunotherapy, AuNPs have shown promise in several applications.

• (1)Antigen delivery: AuNPs can serve as efficient carriers for tumor-associated antigens, enhancing their uptake by antigen-presenting cells and stimulating robust immune responses.^85,86
• (2)Photothermal immunotherapy: the ability of AuNPs to generate heat upon NIR light irradiation has been exploited for combined photothermal and immunotherapy approaches.^87,88,89
• (3)Immune checkpoint modulation: AuNPs have shown potential in enhancing the delivery and efficacy of immune checkpoint inhibitors.^67,87
• (4)Radiotherapy enhancement: the high atomic number of gold makes AuNPs effective radiosensitizers. This property has been exploited to enhance the immunostimulatory effects of radiotherapy.⁹⁰

Magnetic nanoparticles

Magnetic nanoparticles, particularly iron oxide nanoparticles, offer unique advantages for cancer immunotherapy due to their magnetic properties and biocompatibility. In lung cancer immunotherapy, magnetic nanoparticles have been explored for various applications.

• (1)Magnetic hyperthermia: magnetic nanoparticles can generate heat when exposed to an alternating magnetic field, allowing for localized hyperthermia treatment. This approach can be combined with immunotherapy to enhance anti-tumor immune responses.^91,92,93
• (2)Cell tracking: magnetic nanoparticles can be used to label immune cells for non-invasive tracking using magnetic resonance imaging (MRI). This approach has shown potential in monitoring the migration and persistence of adoptively transferred T cells in lung cancer immunotherapy.^91,94
• (3)Targeted delivery of immunomodulators: the magnetic properties of these nanoparticles can be exploited for targeted delivery of immunotherapeutic agents to lung tumors.^68,95,96

Mesoporous silica nanoparticles

MSNs have gained attention in cancer immunotherapy due to their high surface area, tunable pore size, and ease of surface functionalization. In lung cancer immunotherapy, MSNs have shown promise in several applications:

• (1)Co-delivery of immunomodulators: the porous structure of MSNs allows for efficient loading and controlled release of multiple immunotherapeutic agents.^97,98,99
• (2)Antigen delivery: MSNs can serve as effective carriers for tumor-associated antigens, enhancing their uptake by antigen-presenting cells.^98,100
• (3)Stimuli-responsive drug release: MSNs can be designed to release their cargo in response to specific stimuli in the tumor microenvironment.^101,102

To summarize the unique properties and potential applications of various nanomaterials in lung cancer chemotherapy, Table 2 provides a comparative overview of their advantages and disadvantages, along with examples of each type. This table serves as a reference point for understanding the diverse roles that nanomaterials can play in enhancing chemotherapy efficacy and overcoming its limitations. Figure 1 schematically represents innovative nanoparticle-based strategies for enhancing lung cancer therapy. The diagram encapsulates the targeted mechanisms of various nanoparticle systems discussed throughout the review, illustrating their potential to overcome drug resistance, enhance therapeutic efficacy, and minimize side effects.

Table 2.

Advantages and disadvantages of various nanomaterials for lung cancer therapy

Nanomaterial Type	Advantages	Disadvantages	Examples
Organic nanomaterials
Polymeric Nanoparticles	Biocompatible, biodegradable, versatile, controlled drug release, can encapsulate hydrophilic and hydrophobic drugs, tunable surface for targeting, high drug loading capacity.	Potential for aggregation, potential toxicity, rapid clearance by the reticuloendothelial system (RES), manufacturing challenges.	PLGA nanoparticles, PEG nanoparticles, chitosan nanoparticles.
Liposomes	Biocompatible, can encapsulate both hydrophilic and hydrophobic drugs, can be surface-modified for targeting, relatively easy to prepare, stimuli-responsive drug release.	Potential instability, rapid clearance by the RES, potential immunogenicity, challenging to load certain drugs.	Doxil, Myocet, paclitaxel-loaded liposomes.
Lipid Nanoparticles (LNPs)	Efficient delivery of nucleic acids (e.g., mRNA, siRNA), high encapsulation efficiency, biocompatible, relatively stable, potential for surface modification for targeting.	Potential toxicity, immunogenicity, stability issues, challenging for large molecule delivery.	mRNA vaccines, siRNA-loaded lipid nanoparticles.
Inorganic nanomaterials
Metallic Nanoparticles	Unique optical, magnetic, and thermal properties, potential for imaging, photothermal therapy (PTT), and photodynamic therapy (PDT), high drug loading capacity.	Potential toxicity, accumulation in organs, oxidative stress, challenging to clear from the body.	Gold nanoparticles, iron oxide nanoparticles, silver nanoparticles.
Mesoporous Silica	High surface area, tunable pore size, stimuli-responsive drug release, efficient co-delivery of multiple agents, biocompatible.	Potential for aggregation, toxicity concerns, long-term effects not fully understood, challenging to functionalize.	Mesoporous silica nanoparticles (MSNs) for doxorubicin delivery.
Hybrid Nanomaterials	Combine the advantages of different nanomaterials, multifunctional platforms for combination therapies, can be designed for synergistic effects (e.g., chemotherapy + phototherapy).	Increased complexity in design and manufacturing, potential for unexpected interactions between components, potential toxicity.	Gold nanorods functionalized with platinum(IV) prodrugs, polymer-coated metallic nanoparticles.
Biomimetic Nanomaterials	Natural carriers for intercellular communication, low immunogenicity, inherent targeting ability, can evade immune clearance, potential for personalized therapy.	Isolation and purification challenges, batch variability, limited loading efficiency, potential off-target effects.	Neutrophil membrane-coated nanoparticles, cancer cell membrane-coated nanoparticles.

The table delineates the attributes and inherent challenges associated with the application of distinct nanomaterial classes in lung cancer therapeutics. It underscores the specific benefits each nanomaterial offers, such as biocompatibility and targeted drug delivery, alongside the limitations that may include issues like immunogenicity and manufacturing complexities. The table also references exemplary instances of each nanomaterial type, illustrating their practical implementation in enhancing chemotherapy, phototherapy, and immunotherapy strategies for lung cancer. This comparative overview serves as a framework for discerning the potential roles and considerations of nanomaterials in advancing precision cancer treatments.

Figure 1.

Schematic representation of innovative nanoparticle-based strategies for enhancing lung cancer therapy

The diagram illustrates various nanoparticle systems and their targeted mechanisms: CA-MNPS + TSLPS for magnetic targeting and near-infrared photothermal effects, LT-NPs inducing immunogenic cell death, SSL2 facilitating directional targeting, and GO contributing to cytoskeletal disruption. Additionally, GNR@polyPt(IV) enhances photothermal therapy, while PEG-M-PPMT + Ce6 leverages laser irradiation for improved drug accumulation and release. These approaches exemplify the potential of nanomaterials to overcome drug resistance, enhance therapeutic efficacy, and minimize side effects in lung cancer treatment.

Challenges and limitations of nanomaterial-based therapies

While the potential of nanomaterials in lung cancer treatment is undeniable, several significant challenges must be addressed to realize their full therapeutic potential. These challenges span from fundamental biological interactions to practical considerations of scale-up and manufacturing.

Biological barriers and tumor penetration

One of the most significant obstacles in nanomaterial-based cancer therapy is overcoming biological barriers to achieve effective tumor penetration. The EPR effect, long considered a cornerstone of nanoparticle-mediated drug delivery, has recently come under scrutiny. Studies have shown that the EPR effect is highly heterogeneous across different tumor types and even within the same tumor.

In lung cancer, the dense stromal environment and heterogeneous vasculature pose particular challenges for nanoparticle penetration. Recent work by Cheng et al. demonstrated that despite extensive engineering efforts to improve nanoparticle delivery efficiency, the average and median delivery efficiencies remain low, at 1.48% and 0.70% of the injected dose (%ID), respectively. Data analyzed using physiologically based pharmacokinetic models also showed that the delivery efficiency of nanomedicines to tumors at the final sampling time point had average and median values of 2.23% and 0.76% ID, respectively, which are still quite low.¹⁰³ This limited delivery efficiency significantly hampers the therapeutic efficacy of nanomaterial-based treatments.

To address this issue, researchers are exploring various strategies to enhance tumor penetration. One promising approach involves the use of tumor-penetrating peptides (TPPs) conjugated to nanoparticles. These peptides can bind to specific receptors overexpressed on tumor cells, facilitating active targeting and improved penetration.¹⁰⁴

Another innovative strategy involves the use of enzyme-responsive nanoparticles that can change their size or charge in response to tumor-specific enzymes. Multiple studies have shown that matrix metalloproteinases (MMPs) are highly expressed in tumor tissues and can serve as effective targets for triggering nanoparticle responses. For example, MMP-responsive gelatin nanoparticles have been developed for lung cancer therapy. These nanoparticles can control drug release in the presence of MMPs, thereby enhancing therapeutic efficacy.^105,106

Immunogenicity and complement activation

The interaction between nanomaterials and the immune system represents a double-edged sword in cancer therapy. While some degree of immune stimulation can enhance anti-tumor responses, excessive activation of the immune system can lead to rapid clearance of nanoparticles and potentially harmful inflammatory reactions.

Complement activation is a particular concern with many nanomaterial formulations. The complement system, a key component of innate immunity, can recognize nanoparticles as foreign entities, leading to their opsonization and rapid clearance by phagocytic cells. This phenomenon, known as the accelerated blood clearance (ABC) effect, can significantly reduce the circulation time and therapeutic efficacy of nanomedicines.^107,108,109

Recent studies have shown that the surface chemistry of nanoparticles plays a crucial role in determining their immunogenicity. For instance, some studies have demonstrated that PEGylation, a common strategy to reduce protein adsorption and increase circulation time, can paradoxically induce complement activation through the lectin pathway.^107,110 This finding has prompted researchers to explore alternative stealth coatings, such as zwitterionic polymers, which have shown promising results in reducing complement activation while maintaining long circulation times.¹¹¹

Furthermore, the potential for nanomaterials to induce adaptive immune responses, including the generation of anti-PEG antibodies, poses challenges for repeated administrations of nanoparticle-based therapies. Strategies to mitigate these immune responses, such as the use of tolerogenic nanoparticles or the development of less immunogenic surface coatings, are active areas of research.

Scalability and manufacturing challenges

The translation of nanomaterial-based therapies from bench to bedside is often hindered by challenges in scalability and manufacturing. Many promising nanoparticle formulations developed in academic laboratories are difficult to produce at the scale and quality required for clinical testing and commercial production.

One key challenge is maintaining consistent physicochemical properties, such as size distribution, surface charge, and drug loading, across different production batches. Even minor variations in these parameters can significantly affect the biodistribution, efficacy, and safety profile of nanomedicines. To address this issue, regulatory agencies have implemented stringent quality control requirements for nanomaterial-based products.

Advanced manufacturing techniques, such as microfluidics and continuous flow reactors, are being explored to improve the scalability and reproducibility of nanoparticle production. These methods offer better control over reaction conditions and can produce nanoparticles with more uniform characteristics compared to traditional batch processes.

Another significant challenge is the development of analytical methods capable of accurately characterizing complex nanomaterial formulations. Traditional analytical techniques may not be sufficient to fully characterize the unique properties of nanomedicines. This has led to the development of specialized analytical approaches, such as asymmetric flow field-flow fractionation (AF4) coupled with multi-angle light scattering (MALS), which can provide detailed information on size distribution, drug loading, and stability of nanoparticle formulations.^112,113,114

Regulatory considerations

The regulatory landscape for nanomaterial-based therapies is complex and evolving. Regulatory agencies, such as the FDA and European Medicines Agency (EMA), are working to develop appropriate frameworks for evaluating the safety and efficacy of nanomedicines. However, the unique properties of nanomaterials often challenge traditional regulatory paradigms.

One key issue is the lack of standardized definitions and characterization methods for nanomaterials across different regulatory jurisdictions. This can lead to inconsistencies in how nanomedicines are classified and evaluated. Efforts are underway to harmonize regulatory approaches, but significant work remains to be done. Another challenge is determining appropriate preclinical testing requirements for nanomaterial-based therapies. Traditional toxicology studies may not fully capture the unique biological interactions of nanomaterials. As a result, regulatory agencies are increasingly requesting specialized studies, such as detailed biodistribution analyses and long-term toxicity assessments, for nanomedicine applications. The complexity of nanomaterial-based combination products, which may incorporate both drug and device components, also presents regulatory challenges. These products often fall under multiple regulatory categories, requiring coordinated review processes across different agency divisions.

Despite these challenges, progress is being made in establishing clearer regulatory pathways for nanomedicines. The FDA’s Nanotechnology Task Force and the EMA’s Expert Group on Nanomedicines are working to develop guidance documents and refine regulatory approaches specific to nanomaterial-based therapies.

Conclusion

Lung cancer remains a significant global health challenge due to its high incidence and mortality rates. Despite advancements in conventional therapies, their efficacy is often limited by systemic toxicity, drug resistance, and insufficient tumor specificity. Nanomedicine offers innovative solutions by leveraging the unique physicochemical properties of nanomaterials to enable precise drug delivery, combination therapies, and immune modulation. Applications of nanomaterials in chemotherapy, phototherapy, and immunotherapy have demonstrated substantial promise, particularly in overcoming drug resistance and enhancing therapeutic outcomes. However, challenges such as biological barriers, immunogenicity, scalability in manufacturing, and regulatory complexities continue to hinder clinical translation.

Future efforts should focus on innovative design strategies, advanced manufacturing technologies, and interdisciplinary collaboration to address these limitations and accelerate the clinical application of nanomedicine in lung cancer treatment. While challenges remain, nanomedicine holds transformative potential to revolutionize lung cancer therapy, ultimately improving patient survival and quality of life.

Declaration of interests

The authors declare no competing interests