Precision Multimodal Nanodynamic Therapy for Lung Cancer: From Tumor Microenvironment-Responsive Platforms to Cell-Death Reprogramming and Immune Remodeling

Abstract

Lung cancer remains one of the most prevalent and lethal malignancies worldwide and is characterized by a complex tumor microenvironment (TME), including severe hypoxia, acidosis, elevated glutathione levels, and pronounced immunosuppression. These pathological conditions compromise the efficacy of conventional therapies and contribute to drug resistance, tumor recurrence, and metastasis. Nanodynamic therapy (NDT) is an emerging therapeutic paradigm that employs nanomaterials to amplify reactive oxygen species (ROS) generation in response to endogenous or exogenous stimuli, thereby enabling localized tumor ablation and immune reprogramming. This review systematically summarizes the biological basis of NDT in lung cancer. Particular emphasis is placed on the sequential biological processes of TME responsiveness, programmed cell death (PCD) pathway reprogramming, and immune remodeling. We comprehensively review the therapeutic applications and translational potential of four major NDT modalities—sonodynamic therapy (SDT), chemodynamic therapy (CDT), photodynamic therapy (PDT), and radiodynamic therapy (RDT)—in lung cancer. We further highlight recent advances in the integration of these modalities with lung cancer–specific therapeutic strategies. These advances include immunogenic cell death (ICD)-mediated conversion of immunologically “cold” tumors into “hot” tumors, as well as synergistic strategies incorporating EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, anti-angiogenic treatment, and inhalable pulmonary delivery systems. Finally, we critically examine major barriers to the clinical translation of NDT, including the limited availability of clinically relevant in situ models, inadequate material consistency, insufficient long-term pulmonary toxicity data, and the lack of standardized physical activation parameters. We further propose priorities for future research and clinical translation. Collectively, this review provides a systematic and integrative framework for lung cancer NDT, spanning mechanistic design, therapeutic optimization, and potential clinical translation.

Introduction

Lung cancer is among the malignant tumors with the highest global incidence and mortality, and its disease burden continues to rise. According to the latest estimates from GLOBOCAN 2022, there are approximately 2.48 million new lung cancer cases and 1.82 million related deaths worldwide. The age-standardized incidence and mortality rates are 23.6 per 100,000 and 16.8 per 100,000, respectively.¹ In China, lung cancer accounted for 1.06 million new cases and 0.73 million deaths in 2022, with age-standardized incidence and mortality rates of 40.8 and 26.7 per 100,000 (1.7-fold and 1.6-fold higher than global averages, respectively).² Notably, epidermal growth factor receptor (EGFR) mutations are present in approximately 48.7% of Chinese non-small cell lung cancer (NSCLC) patients, with exon 19 deletion and L858R mutations being the most prevalent subtypes.³ Moreover, MET amplification, a major mechanism of acquired resistance to third-generation EGFR-TKIs, has been detected in 7%–18% of patients progressing on osimertinib, underscoring the urgent clinical need for resistance-overcoming therapeutic strategies. In addition, the C797S tertiary mutation represents another critical on‑target resistance mechanism against osimertinib. It occurs in 10–26% of first‑line and 30–40% of second‑line progressive patients. Currently, no effective targeted therapy exists for this mutation. This gap further underscores the necessity of exploring ROS‑based nanodynamic strategies to overcome resistance. The incidence and mortality of lung cancer in China and the United States are expected to continue increasing significantly by 2050.¹ Among histological types, NSCLC accounts for approximately 84%–85% of all lung cancers.⁴ Its high proportion, combined with a poor prognosis, poses a serious public health challenge. In recent years, the treatment pattern of lung cancer has undergone profound changes due to a series of means, such as advanced surgery, widespread radiotherapy, standardized platinum based dual drug chemotherapy, molecular targeted drug iteration, and the application of immune checkpoint inhibitors.⁵ However, current therapeutic approaches still encounter numerous limitations. Molecular targeted therapy frequently leads to drug tolerance, persistent cell survival and acquired resistance.⁶ Immunotherapy is constrained by the immunosuppressive tumor microenvironment and primary resistance. Although surgery, radiotherapy, and chemotherapy can achieve local tumor control, the reported risk of local recurrence remains approximately 20%–50%, depending on disease stage, treatment modality, and follow-up duration, particularly in resected early-stage disease and locally advanced NSCLC treated with definitive chemoradiotherapy.⁷ These treatments are also accompanied by severe systemic side effects and impaired quality of life.⁸ More importantly, the lung cancer TME exhibits key characteristics such as hypoxia, acidic pH, high glutathione (GSH) levels, and dense extracellular matrix. These characteristics not only promote tumor invasion and metastasis but also severely compromise the efficacy of conventional therapies and induce immune escape.⁹ Therefore, relying solely on a single treatment modality makes it difficult to break the vicious cycle of drug resistance, metastasis, and recurrence. There is an urgent need for novel combination strategies that can simultaneously achieve local precision ablation and systemic immune activation in clinical practice.

In recent years, the field of NDT for lung cancer has expanded rapidly. It encompasses multiple treatment modalities, including PDT, RDT, SDT, and CDT.¹⁰ Its core principle involves using nanomaterials to amplify the generation of ROS and reactive nitrogen species (RNS) under endogenous tumor stimulation or exogenous energy, thereby inducing selective tumor damage. This approach covers the design of efficient nanosensitizers, tumor-targeted delivery strategies, and integration with synergistic therapies (eg, immunotherapy), highlighting unique advantages for novel lung cancer treatment. Unlike simple drug delivery, NDT integrates nanocatalysis, energy conversion, TME response, and immune regulation into a single therapeutic platform, offering a novel technological pathway to overcome the complex lung cancer microenvironment.^11,12 Anatomically, lung cancer lesions are often located in the lung parenchyma, bronchial lumen, or near the mediastinum. This localization poses severe pulmonary toxicity challenges for systemic therapies such as chemotherapy, targeted therapy, and immunotherapy.¹³ Therefore, compared with traditional systemic treatments that carry high toxicity, locally controllable energy activation methods are theoretically more suitable for achieving precise tumor targeting while maximizing protection of normal lung tissue and respiratory function.¹⁴ NDT precisely meets this clinical demand (Figure 1).

Figure 1.

Classification and Mechanisms of Nanodynamic Therapy. Schematic illustration of four major NDT modalities. PDT: light-activated ROS generation, limited by tissue penetration depth (visible light: mm scale; NIR-I: ~1 cm). RDT: X-ray/γ-ray activation, enabling deep tissue penetration. SDT: ultrasound activation (20–100 kHz), penetrates >5 cm with minimal attenuation. CDT: endogenous TME-driven catalysis utilizing H₂O₂ and acidic pH, independent of external energy input. SDT and RDT overcome thoracic barriers for deep lesions; CDT functions independently of tumor location. Adapted from Li Y, Jin L, Tao B, et al Nanodynamic therapy for cancer: mechanistic innovations, targeting strategies and multimodal treatments. J Transl Med. Copyright © 2025 by Li et al.¹⁵

These approaches are systematically combined into an integrated NDT system.¹⁶ They can be collectively defined as a therapeutic strategy that uses endogenous or exogenous energy to activate nanoplatforms and intensify reactive oxygen species, reactive nitrogen species or metal-catalyzed damage within tumor tissues.¹⁶ NDT activates nanosensitizers by locally producing ROS or other cytotoxic intermediates and reprogramming the immunosuppressive microenvironment to an immune-activated state,¹⁷ ultimately achieving precise tumor cell clearance.^18,19 But when applied alone, each of these modalities faces significant clinical translation bottlenecks. The penetration depth of PDT light is insufficient to reach deep tumor lesions,²⁰ and the hypoxic tumor microenvironment severely weakens its oxygen-dependent ROS generation efficiency;²¹ SDT commonly faces issues such as insufficient tumor enrichment;²² RDT is constrained by hypoxic radiation resistance resulting from tumor heterogeneity and abnormal vascular distribution.²³ As for CDT, its catalytic efficiency is severely limited by three factors: insufficient concentration of endogenous hydrogen peroxide (H₂O₂) in tumors, precipitation-induced deactivation of Fe³⁺ at physiological pH, and spatial heterogeneity of the acidic microenvironment.²⁴ Leveraging the unique physicochemical properties of nanomaterials, nanomedicine offers a new direction for breakthroughs in NDT-based diagnosis and treatment of lung cancer. For example, upconversion nanoparticles (UCNPs) can convert near-infrared light into visible light to activate deep-seated photosensitizers, while nanocomponents such as manganese dioxide catalyze the in situ decomposition of H₂O₂ within tumors to produce oxygen, thereby alleviating hypoxia and restoring ROS generation efficiency.²⁵ Hollow mesoporous titanium dioxide, metal oxide nanoparticles, and biomimetic cell membrane-coated nanoplatforms have achieved tumor-specific enrichment through homologous targeting or ligand modification.²⁶ In the field of RDT, high-Z element nanoparticles enhance local radiation energy deposition and Compton scattering effects, thereby improving tumor radiosensitivity while reducing systemic radiation dose. Additionally, oxygen-loaded nanocarriers reverse radiation resistance by improving tumor oxygenation status.²³ Regarding CDT, recent research has overcome bottlenecks such as insufficient H₂O₂ and Fe³⁺ precipitation in the TME by optimizing nanocatalyst composition and structure. This significantly enhances the ROS amplification effect.²⁷

At present, several reviews have discussed tumor therapies based on nanotechnology and energy dependence, focusing on the basic mechanisms and general strategies of modalities such as PDT and SDT.^16,28,29 Nevertheless, targeted and in depth analysis of nanodynamic therapies for lung cancer remains lacking. This tumor has a unique anatomical location. Notably, existing reviews have not sufficiently addressed lung-cancer-specific challenges. They rarely explore the potential of inhalable local delivery systems or the synergistic application of ferroptosis and cuproptosis in the pulmonary microenvironment.³⁰ Moreover, a comparative assessment of tissue penetration and ROS generation efficiency across PDT, SDT, CDT, and RDT modalities remains lacking. This review explores the biological mechanisms underlying nanodynamic therapy for lung cancer. It synthesizes the sequential biological processes including TME response, death pathway reprogramming and immune transformation, and summarizes research advances across various nanodynamic treatment modalities. At the same time, it lists several combination therapy methods, highlighting the interdisciplinary and distinctive nature of current cancer research. Finally, it critically analyzes the challenges hindering the clinical translation of nanodynamic materials and proposes innovative solutions and unique perspectives. By addressing these gaps, the present review aims to provide a more precise and clinically relevant framework for lung cancer nanodynamic therapy. Our aim is to provide new ideas and insights for lung cancer treatment.

Biological Basis of Nanodynamic Therapy for Lung Cancer

Tumor Microenvironment and Nanodynamic Therapy for Lung Cancer

TME exhibits pathological features that differ significantly from those of normal lung tissue. These include hypoxia, acidification, high interstitial pressure, vascular abnormalities, inflammatory disorders, excessive accumulation of endogenous H₂O₂, high GSH expression, and profound immunosuppression (Figure 2). These features collectively form the biochemical basis for tumor progression, metastasis, and treatment resistance.^31,32

Figure 2.

Tumor microenvironment of lung cancer. TME is composed of various cells and molecules, and immune suppressive cells interact with tumor cells through multiple molecular pathways to form characteristics such as hypoxia, acidification, interstitial hypertension, vascular structural abnormalities, chronic inflammation, and immune suppression. Adapted from Wang L, Zhang L, Zhang Z, Wu P, Zhang Y, Chen X. Advances in targeting tumor microenvironment for immunotherapy. Front Immunol. Copyright© 2024 by Wang et al.³³

However, these “pathological” features provide a unique endogenous activation window for NDT. The hypoxic state activates various transcription programs by stabilizing hypoxia-inducible factor-1α (HIF-1α) and HIF-2α, thereby promoting glycolysis, angiogenesis, epithelial–mesenchymal transition, and immune escape.³⁴ The weakly acidic environment and overexpressed H₂O₂ serve as ideal catalysts and substrates for Fenton and Fenton-like reactions in CDT.³⁵ Metal nanoparticles such as iron, copper, and manganese can convert low toxicity H₂O₂ in tumors into highly toxic hydroxyl radicals (·OH). This amplifies ROS mediated damage.³⁶ The reducing capacity of GSH also provides a redox-responsive design approach for nanoplatforms. For example, Cu²⁺, manganese dioxide (MnO₂), and Fe³⁺ achieve GSH depletion through redox reactions with GSH, accompanied by the reduction of metal ion valence states. This not only removes the antioxidant barrier but also enhances the catalytic efficiency of Fenton and Fenton-like reactions.³⁷ In addition, the immune “cold” microenvironment in lung cancer TME—characterized by infiltration of immunosuppressive cells (eg, regulatory T cells and tumor-associated macrophages) and high expression of immune checkpoint molecules—limits spontaneous activation of the anti-tumor immune response. However, it also creates a substantial therapeutic window for achieving “cold-to-hot” immune transformation following immunogenic cell death induced by NDT, thereby enhancing anti-tumor immunity (Figure 3).³⁸

Figure 3.

TME-driven strategies for converting cold lung tumors into hot tumors. In the tumor microenvironment, immunosuppressive cells, abnormal metabolism, intercellular communication barriers, physical and biochemical barriers, and vascular abnormalities collectively limit anti-tumor immune responses, resulting in a typical “cold tumor” state. Strategies that target regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Tumor-Associated Macrophages (TAMs) can regulate immune suppression and activate dormant immune pathways involving NK cells, B cells, dendritic cells (DCs), and T cells. When combined with vascular remodeling, extracellular matrix (ECM) degradation, cancer-associated fibroblast (CAF) reprogramming, metabolic regulation, and immune network co-activation, these approaches promote immune cell infiltration and enhance both adaptive and innate immune responses. Consequently, the immunosuppressive “cold” microenvironment of lung cancer can be transformed into an immunostimulatory “hot” microenvironment. This transformation provides a strategic basis for immune conversion induced by NDT and for precise combination therapy. Adapted from Yu J, Kong X, Feng Y. Tumor microenvironment-driven resistance to immunotherapy in non-small cell lung cancer: strategies for Cold-to-Hot tumor transformation. Cancer Drug Resist. Copyright © 2025 by Yu et al.³⁹

Nonetheless, this seemingly adaptive pathological landscape also constitutes a key bottleneck for the efficacy of NDT. Hypoxia is a common feature of solid tumors. It severely restricts oxygen dependent modalities such as PDT, SDT, and radiation therapy. These therapies rely on oxygen to generate singlet oxygen (¹O₂) or free radicals. In hypoxic areas, PDT efficiency is significantly impaired.⁴⁰ SDT itself also consumes substantial oxygen, further exacerbating tumor hypoxia and creating a vicious cycle of treatment resistance.⁴¹ On the other hand, GSH is the main endogenous antioxidant. Its overexpression in tumor cells can directly scavenge ROS generated by nanodynamic therapy. This significantly weakens the net oxidative damage and offsets the therapeutic effect.³⁸ In addition, the immunosuppressive properties of the TME not only hinder immune-mediated recognition and clearance of tumor cells but also prevent NDT-induced immunogenic cell death from effectively transforming into a sustained systemic anti-tumor immune response. This can lead to post-treatment recurrence and metastasis.⁴² Therefore, the lung cancer TME serves not only as a unique endogenous trigger for NDT but also as a barrier to its therapeutic efficacy.

Nanodynamic Therapy Induces Key Cell Damage and Programmed Cell Death

ROS is an inevitable byproduct of cellular metabolism and exert dynamic effects on the tumor growth microenvironment.⁴³ The “double-edged sword effect” of ROS is reflected in their excessive accumulation, which leads to increased oxidative stress, damage to cellular biomacromolecules (eg, nucleic acids, proteins, and lipids), and promotion of tumorigenesis. However, as ROS concentration increases, both endogenous and exogenous ROS can mediate the activation of various pro-apoptotic signals, thereby inducing tumor cell death.⁴⁴ Therefore, NDT adopts a pro-oxidative pathway to generate large amounts of ROS/RNS, disrupting the cellular redox balance and thereby exerting anti-tumor effects. The ROS/RNS generated by NDT are not simply end-stage toxic molecules. Instead, they act as first messengers to initiate a series of subcellular damage responses. First, ROS/RNS can disrupt mitochondrial membrane potential, leading to oxidative phosphorylation uncoupling and ATP synthesis disruption, thereby releasing pro-apoptotic factors.¹ Shi et al constructed an acid-responsive PLM/PPA/β-Lap nanosystem that utilizes tumor-specific high expression of NQO1 to catalyze substantial ROS generation from β-Lap. This further induces NO release and in situ production of peroxynitrite (ONOO⁻), ultimately leading to DNA damage and mitochondrial dysfunction, thereby hindering tumor metastasis.⁴⁵ In addition, excessive ROS can increase lysosomal membrane permeability (LMP), promoting leakage of proteases (eg, cathepsin B) into the cytoplasm and activating non-caspase-dependent lysosomal cell death pathways, which are distinct from classical PCD pathways.⁴⁶ At the same time, ROS triggers a chain reaction of lipid peroxidation by extracting hydrogen atoms from membrane phospholipids. This process not only directly damages the integrity of cell membranes and organelles,⁴⁷ but also generates highly ·OH in lysosomes via the Fenton reaction, further exacerbating membrane damage.⁴⁸ In a study by Wang et al, two-dimensional Ca₂Mn₈O₁₆ nanosheets (CMO NSs) were shown to consume glucose in the acidic TME to generate H₂O₂, which then catalyzes the conversion of H₂O₂ to ·OH, while depleting GSH and inhibiting glutathione peroxidase 4 (GPX4) activity. This leads to the accumulation of lipid peroxides (LPO) in lung cancer cells, thereby triggering ferroptosis, a key iron-dependent PCD pathway.⁴⁹

The aforementioned subcellular damage does not take place as separate events. These processes interact with each other and produce mutual amplification effects. Specifically, mitochondrial outer membrane permeabilization releases cytochrome c. This substance activates the caspase 3/7/9 cascade and further promotes the classical apoptotic pathway.⁴⁰ When the apoptotic pathway is blocked, mitochondrial ROS can initiate necroptosis via the RIPK1/RIPK3/MLKL signaling axis, thereby clearing drug-resistant cells through programmed necrosis.⁵⁰ High-dose photodynamic therapy can also directly induce non-programmed necrosis.⁵¹ As a non-apoptotic cell death mode driven by iron-dependent lipid peroxidation, ferroptosis is characterized by GSH depletion and GPX4 inactivation, which prevents the reduction of lipid peroxides to non-toxic lipid alcohols and ultimately leads to cell membrane rupture.⁴⁹ In a study by Li et al, Cu₂O@Au cascade catalytic nanoenzymes were reported to induce a “tumor starvation” effect through GOx-like activity, increase H₂O₂ levels, and generate ·OH via a POD-like reaction, while downregulating solute carrier family 7 member 11 (SLC7A11) expression to block cysteine uptake. This creates a positive feedback loop involving ROS amplification, GSH depletion, and ferroptosis.⁴⁹ Notably, cuproptosis has recently emerged as a novel mode of cell death. Copper ions induce protein aggregation and toxic stress by targeting acylated tricarboxylic acid (TCA) cycle proteins within mitochondria (eg, DLAT, FDX1), thereby providing a new target for bypassing traditional apoptosis resistance.⁵² The dendritic mesoporous silicon nanobomb (DNCPID) designed by Fan et al achieved dual supply of superoxide (O₂•⁻) and NO via the Haber-Weiss reaction. The two species then synthesize peroxynitrite (ONOO⁻) in a controlled manner at the tumor site, synchronously inducing upregulation of MMP-2/9. This process breaks down the collagen barrier and induces cuproptosis to aggravate mitochondrial damage. It ultimately realizes therapy combining deep penetration and multimodal synergism.⁵³ In summary, nanodynamic therapy has established a multi-node, multi-pathway cell death regulatory network mediated by ROS/RNS, providing a multidimensional biological basis for overcoming treatment resistance in lung cancer and achieving immune transformation.

Nanodynamic Therapy for Lung Cancer Activates Immune Response and Reshapes the Tumor Ecology

The true value of NDT in lung cancer lies not only in local oxidative killing but also in its immune activation potential to transform “cold” tumors into “hot” tumors.⁵⁴ NDT responds to endogenous and exogenous energy stimuli to generate ROS, induces ICD in tumor cells, and reshapes the TME to reverse immune escape. Ultimately, this achieves local tumor killing and stimulates systemic immune responses, thereby inhibiting tumor recurrence and metastasis. Nevertheless, the immune activation effect of NDT does not occur spontaneously. Its efficacy is greatly restricted by the immunosuppressive network formed by intrinsic cellular components in the TME of lung cancer,³⁹ as well as by specific physicochemical characteristics such as hypoxia and dense matrix barriers.⁵⁵ To address tumor hypoxia, studies have reported that gold nanocages (AuNCs) mediate ROS production as intrinsic inorganic photosensitizers (PS). Moreover, due to local electric fields (LEFs),^56,57 gold nanomedicines can enhance the PDT efficiency of other PS. Based on these principles, Liang et al designed a TME-responsive core–shell nanostructure, AuNC@MnO₂ (AM).⁵⁸ Under acidic TME conditions, the MnO₂ shell degrades and catalyzes the reaction of intracellular H₂O₂ to produce substantial oxygen. This self-generated O₂ further enhances the ROS production of AM under light by alleviating tumor hypoxia. More importantly, compared with PDT alone using AuNCs, oxygen-enhanced PDT induces stronger ICD, thereby enhancing the anti-tumor immune response.^54,58 In addition, Wu et al constructed a poly(lactic-co-glycolic acid) (PLGA) nanoparticle functionalized with epidermal growth factor and co-loaded with 5-fluorouracil and perfluorocarbon (PFC) for targeted cancer therapy.⁵⁹ The results showed that PFC alleviated tumor hypoxia by delivering oxygen to the tumor. Furthermore, Murphy et al⁶⁰ encapsulated MnO₂ nanoparticles (NPs) in PLGA to efficiently catalyze the degradation of H₂O₂ in tumor tissues, thereby generating oxygen. Compared with unencapsulated MnO₂ NPs, PLGA-MnO₂ NPs exhibited better biocompatibility and enhanced penetration, along with reduced expression of hypoxia-inducible factor-1α (HIF-1α). Although the oxygen-generating nanoplatform effectively enhanced the immune response after PDT treatment, the immunosuppressive TME ultimately hindered the efficacy of PDT-mediated cancer immunotherapy by inhibiting cytotoxic T lymphocyte (CTL) activation.⁶¹ To address this issue, Liu et al prepared a light-responsive hydrogel containing Ce6-modified catalase (CAT), degradable PEGDA, and the R837 nanoadjuvant. This induced strong ICD and regulated macrophage polarization.⁶¹ Tumor-Associated Macrophages (TAMs) play a critical role in determining immunotherapy efficacy and are typically classified into anti-tumor M1 and pro-tumor M2 phenotypes.⁶² Studies have shown that the ATONPs@AucRGD + UTMD + laser combination effectively promotes the reprogramming of M2 to M1 macrophages within the TME, thereby remodeling the immunosuppressive microenvironment and enhancing immune killing responses.⁶³ In addition, the light-enhanced CDT mediated by the Cu²⁺-coordinated tetracycline-porphyrin self-assembled nanoplatform (LP/CuTT) induces ICD, significantly promotes dendritic cell (DC) maturation, and reprograms tumor-associated macrophages from the pro-tumor M2 to the anti-tumor M1 phenotype. Ultimately, this enhances the infiltration density of CD8⁺ and CD4⁺ T cells within the tumor.⁶⁴ These “reprogrammed” TAMs promote CTL recruitment and enhance memory T cell-mediated tumor killing. This strategy effectively eradicates tumors, inhibits metastasis, and prevents recurrence, offering promising prospects for effective cancer immunotherapy. Vascular normalization can also reduce the formation of an immunosuppressive microenvironment. To alter the tumor immune microenvironment (TIME) and prevent tumor angiogenesis and progression, Wei et al developed a lipoprotein complex (F-PLP/pBIM). This complex consists of folic acid-personalized liposomes (F-PLP) and a BIM-S plasmid (pBIM), and is designed to simultaneously target cancer cells and folate receptor β-positive TAMs. The results showed that F-PLP/pBIM significantly induced apoptosis of M2 macrophages in LL/2 and A549 tumor models.⁶⁵ In addition, Chen et al⁶⁶ normalized tumor vasculature using erlotinib, which significantly enhanced tumor perfusion and oxygenation in mice, while also reversing the immunosuppressive microenvironment and improving the efficacy of anti-PD-L1 tumor immunotherapy. CAFs are the most abundant stromal cells in the TME. Their excessive activation leads to secretion of large amounts of collagen and formation of a dense stromal barrier, which impedes the infiltration of drugs and immune cells.⁶⁷ One study showed that NO can block TGF-β transduction via the sGC-cGMP pathway.⁶⁸ NO donor-loaded liposomes (Lip-SNAP) inhibit dense stroma production by suppressing TGF-β expression and its downstream pro-fibrotic signaling, thereby enhancing the tumor penetration ability of gemcitabine-loaded liposomes. Because downregulating ECM expression or degrading pre-existing ECM can improve the delivery efficiency of drug delivery systems in tumor tissues, Wang et al⁶⁹ conjugated hyaluronidase onto biocompatible dextran via acid-sensitive bonds to prepare DEX-HAase nanoparticles. When passively targeted to tumor tissues, these nanoparticles loosen the ECM structure and enhance the penetration of oxygen and photosensitizer-loaded liposomes into the tumor, thereby achieving improved tumor immunotherapy outcomes when combined with anti-PD-L1. In summary, the clinical value of NDT in lung cancer depends fundamentally on its ability to overcome the lung cancer microenvironment, achieve the transformation from a “cold” to a “hot” tumor, and activate systemic immune memory.

Progress in the Application of Different Nanodynamic Therapies for Lung Cancer

In recent years, NDT has developed rapidly in lung cancer treatment. The core paradigm is shifting profoundly from single drug delivery to multifunctional intelligent platform integration. This new direction encompasses intelligent response, immune activation, targeted delivery, and energy triggering in a multi module collaborative manner.^70,71 For example, the STRIDE nanoplatform reported by Chen et al achieves precise tumor targeting and responsive endosomal/lysosomal release through rational peptide modification, successfully co-delivering siGLI1 and a cisplatin prodrug. The results showed that in a lung adenocarcinoma resistance model, the tumor regained sensitivity to chemotherapy drugs, demonstrating the dual advantages of intelligent response and targeted delivery.⁷² At the level of immune activation, a biomimetic coating of Fe₃O₄ nanoparticles based on the macrophage membrane was constructed—the HMME@MPs platform. This platform utilizes the natural recognition properties of immune cell membranes to achieve efficient tumor targeting, while synchronously inducing ferroptosis and sonodynamic effects under US stimulation. It thereby effectively demonstrates the feasibility of synergistically integrating NDT with immune regulation.⁷³ Zhang et al further designed a multifunctional apigenin-based nanoplatform that combines metabolic regulation with photodynamic perturbation. On one hand, it reshapes the immunosuppressive microenvironment by inhibiting glycolysis; on the other hand, it destroys mitochondria and the endoplasmic reticulum by targeting photosensitizers to dual organelles. In a mouse model of non-small cell lung cancer, the platform achieved a tumor inhibition rate of 97% for primary lesions and 80% for distant metastases, fully demonstrating the enormous potential of NDT platforms to enhance treatment depth through metabolic, photodynamic, and immune multi-pathway synergy.⁷⁴ Notably, recent research has also created local administration strategies based on inhalation NDT platforms. The LMS nanoplatform designed by Wang et al achieved efficient accumulation of ferroptosis inducers in lung cancer via nebulization delivery. By utilizing the multi-enzyme catalytic activity of nanoenzymes to trigger oxidative stress storms and lipid peroxidation bursts, this platform promotes dendritic cell maturation and enhances T cell immune responses while inducing ferroptosis. This design not only significantly increases local drug concentration but also effectively avoids systemic toxic side effects.⁷⁵ Recently, Liu et al developed a tumor‑cell‑membrane‑coated nanozyme. This nanozyme generates oxygen and delivers curcumol. It achieves precise catalytic therapy for lung cancer. The approach follows a “source‑saving and expenditure‑reducing” strategy. It shows excellent tumor suppression in subcutaneous and orthotopic lung cancer models.⁷⁶ The LMS platform has demonstrated that local drug delivery for NDT in lung cancer does not rely solely on intravenous injection. Instead, it can be achieved through non invasive administration routes (such as respiratory inhalation, microneedles, and even dry powder inhalers) to achieve precise accumulation and controlled release in lung lesions. This provides a more feasible administration paradigm for the clinical translation of NDT. In addition to immune activation, multimodal integration of energy-triggered mechanisms is also a prominent focus in current NDT platform design. Liao et al constructed a GSH-responsive polycarbonate nanoplatform that co-delivers a NO donor and the acoustic sensitizer chlorin e6 (Ce6). When triggered to disintegrate by high concentrations of GSH in tumor cells, the platform released NO, which alleviated hypoxia by downregulating HIF-1α and synergistically generated highly toxic peroxynitrite (ONOO⁻) with ultrasound-stimulated ROS, thereby significantly amplifying SDT efficacy. The IC₅₀ value was reduced approximately 2.5-fold compared with that of free Ce6.⁷⁷ In addition, Cao et al reported an ultrasound‑responsive DNA nanoflower‑based nanocarrier (DHA‑DDF). This nanocarrier carries hypoxia-inducible factor-1α (HIF-1α) antisense sequences, achieving synergistic hypoxia modulation and sonodynamic therapy in the Lewis lung carcinoma model. It significantly inhibits tumor angiogenesis and prolongs survival.²⁶ This section focuses on four main NDT technologies: SDT, CDT, PDT, and RDT. It systematically explains their unique mechanisms, TME responsive strategies, and immune transformation effects in nanodynamic therapy for lung cancer (Table 1).

Table 1.

Summary of Therapeutic Characteristics of Lung Cancer-Related NDT Nanosensitizers

Nanosensitizer/Nanoplatform	NDT Modality	Lung Cancer Model/Indication	TME-responsive or Targeting Design	Therapeutic Mechanism	Translational Relevance	Source
Ce6–erlotinib carrier-free nanoparticles (EC-NPs)	SDT + EGFR-targeted therapy	NSCLC	Carrier-free self-assembly of chlorin e6 and erlotinib	Ultrasound activates Ce6 to generate 1O2/ROS; erlotinib blocks EGFR/PI3K/AKT signaling, inducing mitochondrial dysfunction and apoptosis	Combines SDT with clinically relevant EGFR inhibition; suitable for EGFR-driven NSCLC	[78]
Ultrasound-driven nanomachine	SDT + immunotherapy	NSCLC	Tumor-targeting biomimetic nanomachine with ultrasound activation	Ultrasound triggers localized ROS generation and lysosomal disruption, promoting tumor antigen release, dendritic-cell activation, and CD8⁺ T-cell recruitment	Links local SDT ablation with systemic antitumor immunity	[79]
Biomimetic anlotinib-loaded FePc-silicate nanoparticles	SDT + anti-angiogenesis + immunotherapy	NSCLC	Biomimetic delivery and dual PD-L1 modulation	FePc-silicate mediates US-triggered ROS production; anlotinib inhibits VEGFR2/JAK2/STAT3 signaling and downregulates PD-L1, enhancing T-cell infiltration	Integrates SDT, anti-angiogenic therapy, and immune checkpoint modulation	[80]
cRGD-targeted gold-based nanoparticles	Low-temperature PTT + SDT	EGFR-TKI-resistant NSCLC	cRGD-mediated tumor targeting	Gold-based nanoparticles enhance mild photothermal effects and SDT-induced ROS, helping overcome EGFR-TKI resistance	Relevant to acquired EGFR-TKI resistance in NSCLC	[81]
Cationic liposomal hydroxycamptothecin + 5-ALA	Chemo-SDT	Metastatic lung cancer	Pulmonary delivery to improve local lung deposition	5-ALA is metabolized to PpIX as an endogenous sonosensitizer; ultrasound-triggered ROS synergizes with hydroxycamptothecin chemotherapy	Demonstrates inhalation/pulmonary delivery as a practical route for lung lesions	[82]
Inhalable immune-activation nanoplatform	Ferroptosis-enhanced NDT + immunotherapy	Lung cancer	Inhalable local delivery to lung tumors	Nanoplatform enhances ferroptosis-mediated immunosensitization, promotes dendritic-cell maturation, and strengthens T-cell immune responses	Highlights inhalable NDT for local accumulation with reduced systemic toxicity	[75]
CLDCu inhalable nanoparticles	CDT + cuproptosis + cGAS–STING immunotherapy	Lung metastasis	Acid-responsive inhalable Cu2⁺/disulfiram release system	Acidic TME triggers Cu2⁺ and disulfiram release to form CuET; Cu⁺ accumulation induces cuproptosis and activates cGAS–STING-mediated immunity	Strong example of lung-localized precision nanomedicine and immune conversion	[83]
Diethyldithiocarbamate–Cu4O3 nanocomplex	Copper-based CDT/cuproptosis-related therapy	NSCLC	Copper nanocomplex responsive to intracellular redox imbalance	Induces mitochondrial dysfunction, telomerase inhibition, oxidative stress, and copper-associated tumor-cell death	Provides a metal-ion strategy for NSCLC cell-death reprogramming	[84]
MgFe2O4@ZOL nanoplatform	CDT + microwave dynamic therapy + selective microwave thermal therapy	Lung cancer bone metastasis	GSH depletion-enhanced Fenton-like catalytic system	Releases iron species under acidic TME, consumes GSH, catalyzes H2O2 to ·OH, and combines microwave-triggered dynamic/thermal effects	Specifically addresses lung cancer bone metastasis and oxidative microenvironment remodeling	[37]
Osimertinib–copper–ICG self-assembled nanomedicine	Chemo-photo-CDT + cuproptosis	NSCLC	Metal–organic coordinated carrier-free assembly	Osimertinib targets EGFR-mutant NSCLC; Cu-mediated Fenton-like reaction amplifies ROS; ICG enables photoactivation; copper overload promotes cuproptosis	Suitable for precision treatment of EGFR-mutant or TKI-resistant NSCLC	[85]
Pulmonary theranostic nanoclusters	CDT + radiation-enhanced ferroptosis	Lung cancer	Pulmonary delivery and imaging-guided nanoclusters	Nanoclusters enhance ROS generation, promote ferroptosis, and sensitize tumors to radiation-mediated oxidative damage	Combines local lung delivery, diagnosis, CDT, ferroptosis, and radiotherapy	[86]
Doxorubicin-conjugated polymeric nanoparticles + 5-ALA	RDT/radiotherapy sensitization + chemotherapy	Lung cancer	Polymeric nanoparticle delivery of doxorubicin combined with 5-ALA	5-ALA-mediated porphyrin accumulation and radiation exposure enhance ROS production; doxorubicin adds chemotherapy-induced DNA damage	Represents radiation-driven ROS amplification for lung cancer combination therapy	[87]
Albumin-modified gold nanoparticles	Radiodynamic/radiosensitization therapy	Lung cancer	Albumin modification improves dispersion and tumor interaction	Gold nanoparticles enhance local radiation energy deposition and ROS-mediated DNA damage	Uses clinically familiar radiotherapy as an external trigger for nanodynamic amplification	[88]
Biodegradable iridium-coordinated nanodrugs	PDT + immunotherapy	Lung cancer	Biodegradable iridium-coordinated nanodrug design	Iridium coordination potentiates PDT-induced ROS and immunogenic cell death, enhancing antitumor immune responses	Connects PDT-mediated oxidative killing with immune remodeling in lung cancer	[89]
Pyropheophorbide-a-loaded PLGA nanoparticles (PPa-PLGA NPs)	PDT	Floating lung cancer cells	PLGA nanoformulation improves hydrophobic photosensitizer dispersion	Light activation of PPa generates ROS to ablate floating lung cancer cells	Potentially useful for residual, disseminated, or exfoliated lung cancer cells	[90]
660 nm-activated polymeric nano-photosensitizer carriers loaded with osimertinib	PDT + EGFR-targeted therapy	NSCLC	Polymeric photosensitizer carrier for osimertinib delivery	660 nm irradiation activates PDT-generated ROS, while osimertinib suppresses EGFR signaling	Combines optical activation with molecularly targeted precision therapy	[91]
Dihydroartemisinin-assisted Ce6 system	PDT + ferroptosis	Lung cancer	DHA-mediated ferroptosis sensitization	DHA inhibits GPX4 and enhances ROS/lipid peroxidation, thereby facilitating Ce6-induced PDT	Demonstrates death-pathway reprogramming from PDT to ferroptosis-enhanced killing	[92]

SDT: The Most Realistic Exogenous Activation Axis for Lung Cancer

SDT uses US to activate sonosensitizers, which in turn generate ROS to kill cancer cells.⁹³ This modality offers several unique advantages, including non-invasiveness, suitability for treating deep-seated tumors, and precise tumor targeting achieved through selective US activation.^94,95 The main mechanisms of cell death in SDT involve cavitation (eg, the generation and rupture of microbubbles)⁹⁶ and thermal effects (Figure 4).^97,98

Figure 4.

Schematic diagram of the anti-tumor mechanism of SDT. As an external energy source, US directly causes mechanical damage and necrosis of tumor cells by inducing acoustic cavitation and thermal effects. On the other hand, activation of sonosensitizers mediates the conversion of oxygen into ROS, such as ¹O₂, which induces various forms of programmed cell death—including apoptosis, pyroptosis, and ferroptosis—through oxidative stress, ultimately achieving multi-pathway synergistic tumor killing. Adapted from Shan Q, Li R, Ying B, et al Organic Sonosensitizers-based SDT with enhanced ROS generation. Ultrason Sonochem. Copyright © 2025 by Shan et al.⁹⁹

Traditional PDT is limited in its ability to effectively treat deep lung tumors due to the shallow penetration depth of light.¹⁰⁰ SDT utilizes low-frequency ultrasound for activation. The penetration depth of ultrasound in tissues far exceeds that of near-infrared light, achieving a significant tumor suppression rate of over 70% in clinical studies.¹⁰¹ Low-frequency ultrasound can penetrate tissues up to several centimeters deep and deliver energy to lesions located deep within the lung parenchyma, adjacent to the mediastinum, or inside the bronchial lumen, without damaging the chest wall or normal lung tissue. This provides a minimally invasive and accessible treatment option for central and peripheral NSCLC.¹⁰² This physical advantage has been robustly validated in representative studies in recent years. Xiao et al delivered 5-aminolevulinic acid (5-ALA) via endotracheal administration, which was metabolized into the endogenous sonosensitizer protoporphyrin IX within lung cancer cells. In vitro experiments showed that this combined chemotherapy–sonodynamic regimen demonstrated stronger tumor cell-killing effects than other single or combination regimens. In vivo studies have also confirmed that this regimen exhibits excellent anti-tumor effects in mouse models of metastatic lung cancer.⁸² Li et al synthesized four BODIPY derivatives (BDP1–BDP4) and systematically evaluated their potential in SDT for the first time. The results showed that BDP4 exhibited excellent acoustic sensitivity and high SDT efficiency against cancer cells and tumors in tumor-bearing mice.¹⁰³

Due to the low ROS yield of sonosensitizers and the complexity of the TME, SDT is still in its infancy and has not yet achieved widespread clinical translation.¹⁰⁴ Nanotechnology provides effective strategies to improve SDT efficacy, specifically by enhancing ultrasound cavitation, improving sonosensitizer delivery, and modulating the TME.^105,106 Incorporating acoustically responsive nanomaterials into SDT enables precise control over drug release and activation, thereby minimizing damage to healthy tissues.^107,108 Currently, nanomaterials used to enhance SDT efficacy are mainly classified into three categories: organic sonosensitizers, inorganic sonosensitizers, and organic–inorganic hybrid sonosensitizers. As an example of organic sonosensitizers, Zhang et al¹⁰⁹ developed an ultrasound-responsive nanosystem with Ce6 as the core. This nanosystem efficiently generates ¹O₂ upon US activation and synergizes with two key effects: tumor enrichment mediated by bridging glycoprotein 3, and burst drug release triggered by perfluoropentane ultrasound phase transition. These combined actions significantly enhance the oxidative killing efficacy of SDT. Meanwhile, Tian et al⁷⁸ created a carrier-free nanoparticle system (EC NPs) based on one-step self-assembly of Ce6 and erlotinib. The system activates Ce6 via ultrasound to generate ROS while releasing erlotinib to exert synergistic chemotherapeutic effects, thereby significantly inducing apoptosis and inhibiting proliferation in NSCLC cells and xenograft tumor models. Inorganic nanomaterials can themselves serve as efficient sonosensitizers, offering advantages such as structural stability, tunable sonosensitizing activity, and ease of functionalization. Ping et al⁷⁹ developed an ultrasound-driven nanomachine featuring a gold nanoparticle core, surface-modified engineered macrophage exosomes, and S11e aptamers. This biomimetic nanoplatform specifically targets NSCLC cells, breaking down lysosomal membranes and releasing tissue proteases upon US activation. Meanwhile, the cleaved tumor antigens effectively activate dendritic cells and recruit CD8⁺ T cells, thereby organically linking local SDT killing with systemic immune activation. In addition, Wang et al¹¹⁰ constructed an efficient composite sonosensitizer system based on reduced graphene oxide (rGO) nanosheets, loaded with zinc oxide (ZnO) and gold (Au) nanoparticles, and surface-modified with polyvinylpyrrolidone (PVP). ZnO nanoparticles generate separated electron–hole pairs upon US activation, while the narrow bandgap structure of rGO promotes electron migration from ZnO to gold nanoparticles. This effectively suppresses electron–hole pair recombination and greatly enhances ROS generation efficiency. Organic–inorganic hybrid sonosensitizers leverage the complementary advantages of both components, effectively overcoming the limitations of single-component systems and achieving synergistic performance enhancement. This provides a foundation for combination therapy of tumors with other treatment modalities. For example, Liu et al⁸⁰ designed a biomimetic nanomedicine (APSNM) composed of a PD-L1 antibody-modified macrophage membrane coating loaded with iron phthalocyanine silicate (FePc silicate) and anlotinib. Anlotinib downregulates intracellular PD-L1 expression by inhibiting the VEGFR2/JAK2/STAT3 pathway, while membrane-surface antibodies block extracellular PD-L1 signaling. Upon US activation, FePc silicate generates ROS and enhances anti-tumor immunity, ultimately promoting CD4⁺ and CD8⁺ T cell infiltration and interferon-γ (IFN-γ) expression. This achieves deep integration of anti-angiogenesis, sonodynamic therapy, and immune checkpoint regulation. Recently, Zheng et al reported aptamer-modified mesoporous silica nanoparticles for NO-enhanced targeted sonodynamic therapy of lung cancer, where aptamer-mediated active targeting enabled tumor-specific accumulation and NO gas synergistically boosted ultrasound-triggered ROS production.¹¹¹ Besides, Wei et al¹¹² developed a novel titanium dioxide (TiO₂)-based sonosensitizer coated with a malignant melanoma cell membrane (B16F10) and functionally modified with programmed death ligand 1 antibody (aPD-L1). This achieves a dual-targeting strategy combining homologous targeting and immune checkpoint blockade with sonodynamic therapy. The nanoplatform first extracts TiO₂-based sonocatalytic nanoparticles coated with the B16F10 melanoma cell membrane, then modifies aPD-L1 antibodies via PEG chains and an EDC/NHS coupling reaction. This yields a functional nanoformulation that combines homologous targeting and immune checkpoint blockade. This nanoformulation achieves tumor-homologous targeted enrichment via the B16F10 cell membrane, while the surface-conjugated aPD-L1 specifically binds to tumor cell PD-L1 and blocks the immunosuppressive pathway. Under US irradiation, the TiO₂ core is activated, catalyzing the generation of abundant ROS within the tumor and inducing tumor cell apoptosis. Furthermore, the synergistic effect of SDT-induced ICD and aPD-L1-mediated immune checkpoint blockade promotes interferon-γ (IFN-γ) secretion and activates systemic anti-tumor immunity, thereby achieving a dual anti-tumor effect combining local killing with systemic immune activation (Figure 5).

Figure 5.

Schematic illustration of the fabrication and antitumor mechanism of a biomimetic dual-targeted nanoplatform for enhanced sonodynamic therapy and immune checkpoint blockade. B16F10 melanoma cell membranes (B16F10M) are employed to coat TiO₂-based sonosensitizing nanoparticles (SCN), followed by PEGylation with DSPE-PEG2000-NH₂ and conjugation of anti-PD-L1 (aPD-L1) via EDC/NHS chemistry to obtain SCN@B16F10M/PEG-aPD-L1. The B16F10 cell-membrane coating enables homologous tumor targeting, whereas surface-conjugated aPD-L1 facilitates PD-L1-mediated immune checkpoint targeting. Upon ultrasound irradiation, the TiO₂-based sonosensitizer generates reactive oxygen species (ROS), inducing oxidative damage and tumor-cell apoptosis. Meanwhile, blockade of the PD-1/PD-L1 axis enhances antitumor immune activation and promotes interferon-γ production, thereby integrating tumor-targeted sonodynamic therapy with immune checkpoint blockade for improved antitumor efficacy. Adapted from Wei X, Feng Z, Huang J, et al Homology and Immune Checkpoint Dual-Targeted Sonocatalytic Nanoagents for Enhancing Sonodynamic Tumor Therapy. ACS Appl Mater Interfaces. Copyright © 2021 by Wei et al.¹¹²

The priority of SDT in lung cancer is not due to a single technological advantage, but rather the synergistic effect of its deep penetration capability and multifunctional design of nano platforms. These research advances not only validate the feasibility of SDT as an exogenous activation axis for lung cancer, but also reveal its key path towards evolving into a local systemic combination therapy paradigm.

CDT: The Core Means of Endogenous Disruption in the Tumor Microenvironment

CDT, as the only endogenous activation mode in nanodynamic therapy systems that does not rely on external energy input, exhibits unique pathological adaptability in the treatment of lung cancer.^113,114 It uses Fenton or Fenton-like agents containing metal ions to generate highly cytotoxic ROS—such as ·OH—within lung cancer cells, thereby inducing apoptosis. The inherent weak acidity (pH 6.5–6.9), excessive accumulation of H₂O₂, and high GSH expression in the lung cancer TME precisely constitute the natural catalytic field and substrate reservoir for Fenton and Fenton-like reactions.¹¹⁵ In recent years, researchers have systematically explored the adaptability and synergistic strategies of CDT in lung cancer through metal ion carrier engineering, nanoenzyme catalytic activity optimization, and ion homeostasis regulation. For example, Wang et al prepared NIR-II-responsive iron-doped carbon nanoparticles (FDCNs) using iron-doped carbon as the matrix via a one-pot hydrothermal method. The obtained material exhibits a mesoporous structure with a particle size exceeding 225 nm and acid-responsive properties. It not only releases iron ions to catalyze the generation of ·OH from H₂O₂ for chemodynamic therapy but also absorbs 1064 nm near-infrared light for photothermal conversion.¹¹⁶ Additionally, Xie et al constructed an integrated theranostic platform of FePd TPP/ADM nanocrystals using a thermal decomposition method, which utilizes ·OH generation from tumor H₂O₂ to achieve chemodynamic therapy. Moreover, the repulsion effect between palladium (Pd) and hydrogen atoms further enhances Fenton oxidation efficiency.¹¹⁷ In another study, Wang et al constructed two-dimensional ultra-thin Cu-TCPP metal–organic framework nanosheets. Under the action of peroxidase-like activity and Cu²⁺ within the nanosheets, the acidic H₂O₂ oxidizes the TCPP ligand to generate peroxide radicals. Based on Russell’s principle, ¹O₂ is selectively generated in situ, while intracellular glutathione is depleted, ultimately leading to efficient targeted tumor cell killing.¹¹⁸ Furthermore, Wang et al first prepared hollow HMnO₂ nanoparticles via PLGA reduction and acetone etching, loaded them with bufalin, and then coated them with a platelet membrane to construct a PLTM-HMnO₂@Bu biomimetic nanoplatform. This platform releases drugs and Mn²⁺ in response to pH and GSH within the tumor microenvironment, achieving both MRI-targeted imaging and ·OH production via a Mn²⁺-mediated Fenton reaction, thereby effectively inhibiting tumors synergistically with chemotherapy.¹¹⁹ Meanwhile, glucose oxidase (GOD) has been loaded into an adenosine triphosphate (ATP)-responsive Fenton system to enhance cancer treatment.¹²⁰ The GOD@ZIF@MPN (metal-polyphenol network) shell is degraded into Fe³⁺ and tannic acid (TA), exposing the internal GOD upon internalization into ATP-overexpressing tumor cells. Subsequently, TA reduces Fe³⁺ to Fe²⁺, and GOD reacts with endogenous glucose to catalyze the Fenton reaction for Fe²⁺, producing abundant H₂O₂.¹²¹

However, the deeper bottleneck of traditional CDT strategies is that simply increasing ·OH production is no longer sufficient to overcome multidrug resistance or establish long-term immune memory in lung cancer treatment. The value of CDT in lung cancer is undergoing a paradigm shift—from merely supplementing ROS to reshaping cell death patterns. Future research will focus on deeply coupling the oxidative stress generated by metal ion catalysis with multiple programmed cell death pathways. For example, in the context of ferroptosis coupling, targeting ferroptosis has become an important strategy for enhancing CDT efficacy, as low expression of GPX4 and FSP1 in lung adenocarcinoma has been shown to be significantly associated with poor patient prognosis.⁸⁴ Specifically, the heterogeneous nanoparticles designed by Yu et al, consisting of uniformly distributed copper and Fe₃O₄, achieved extended ·OH lifetime and sustained ROS generation through intraparticle electron transfer.⁸⁴ In addition, the MgFe₂O₄@ZOL nanoplatform constructed by Shu et al confirms the feasibility of coupling CDT with ferroptosis. This platform releases Fe³⁺ in the acidic tumor microenvironment, which consumes intracellular GSH and catalyzes the generation of ·OH from H₂O₂. It has achieved significant anti-tumor efficacy and bone repair in a lung cancer bone metastasis model.³⁷ Yang et al synthesized amino-functionalized MIL-101 nano metal–organic frameworks (nMOFs) with peroxidase-like activity and a porous structure using aminoterephthalic acid and ferric chloride hexahydrate as raw materials via a solvothermal method. Leveraging the high specific surface area and pore-loading characteristics of the material, they loaded the traditional Chinese medicine monomer dihydroartemisinin (DHA) into its interior, thereby successfully constructing a tumor microenvironment-responsive system—the DHA@MIL-101 nanoplatform. This platform is responsive to degradation within the TME, releasing Fe³⁺/Fe²⁺ and DHA. Fe²⁺ catalyzes the Fenton reaction to produce ·OH, while DHA synergistically generates ·OH, depletes GSH, inhibits GPX4, and induces lipid peroxidation (LPO) accumulation, ultimately triggering ferroptosis and apoptosis (Figure 6).¹²²

Figure 6.

Schematic diagram of the DHA@MIL-101 nanoplatform: preparation and synergistic CDT/ferroptosis therapy mechanism for tumors. (A) Preparation process of the DHA@MIL-101 nanoreactor: MIL-101 was synthesized via a solvothermal method using FeCl₃·6H₂O as the precursor, and then loaded with DHA to obtain DHA@MIL-101. (B) Mechanism of CDT/ferroptosis synergistic therapy triggered by the tumor microenvironment in the DHA@MIL-101 nanoreactor: The nanoreactor degrades under acidic and high-GSH conditions, releasing Fe ions and DHA. Fe ions mediate the Fenton reaction to produce ·OH, which is further amplified by DHA to deplete GSH and inhibit GPX4. This leads to lipid peroxidation (LPO) accumulation and DNA damage, ultimately inducing ferroptosis and apoptosis. Adapted from Yang XX, Xu X, Wang MF, et al A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin. J Nanobiotechnology. Copyright© 2022 by Yang et al.¹²²

The cuproptosis pathway, which develops in parallel with ferroptosis, has become another frontier for CDT coupling due to its unique mitochondrial protein toxicity mechanism. The core mechanism of cuproptosis involves excessive binding of copper ions to thiolated proteins in the tricarboxylic acid (TCA) cycle, leading to loss of iron–sulfur cluster proteins and protein toxicity stress.¹²³ For example, the OIC nanoparticles created by Liu et al are self-assembled from osimertinib, copper ions, and indocyanine green. In NSCLC models, copper ions catalyze the Fenton reaction to generate ROS and deplete GSH, while targeting cuproptosis-related proteins such as FDX1 and lipoic acid synthase. The nanoparticles successfully overcame resistance of EGFR-mutant lung cancer to single tyrosine kinase inhibitor (TKI) therapy while achieving a tumor inhibition rate of up to 99.8%.⁸⁵ The prospective study by Tsvetkov et al elucidated the close relationship between cuproptosis and mitochondrial respiration, as well as the lipoic acid pathway. Subsequent studies have further revealed a significant synergistic effect between ferroptosis and cuproptosis, mediated by a mitochondrial ROS cross-cascade.¹²⁴ Based on this collaborative mechanism, a Cu-MOF nanoplatform has been developed for lung cancer treatment. This platform degrades and releases copper ions within the acidic microenvironment of tumor cell lysosomes. On one hand, it catalyzes the Fenton reaction to generate ·OH, inducing oxidative damage and apoptosis. On the other hand, under the mediation of FDX1, it binds copper ions to the mitochondrial protein DLAT, leading to loss of iron–sulfur cluster proteins and aggregation of thioacylated proteins, ultimately triggering cuproptosis induced by protein toxicity stress.¹²⁵ Existing studies have also documented other collaborative mechanisms. Hu et al designed a biodegradable nanocomposite with variable charge and size that overcomes tumor hypoxia and synergistically amplifies CDT-mediated cuproptosis and ferroptosis through dual disturbances of glycolysis and redox balance. This provides a powerful technical solution for co-activating dual death pathways in the hypoxic microenvironment of lung cancer.¹²⁶ Jiang et al reported CACuPDA that simultaneously induce ferroptosis and cuproptosis through a dual GSH/GPX4 depletion strategy, and synergized with immune checkpoint blockade to significantly enhance antitumor immune responses in lung cancer models.¹²⁷ Furthermore, a functional nanozyme system (CussOMEp) using copper-based nanocarriers loaded with omeprazole inhibited copper efflux while augmenting copper accumulation, synergistically activating cuproptosis and ferroptosis pathways, and in combination with anti-PD-1 antibody markedly suppressed lung metastasis.¹²⁸ In recent years, coupling CDT with broader mitochondrial damage and non-classical death pathways has further expanded the conceptual boundaries of “reshaped death patterns”. A groundbreaking study constructed a porous Fe₃O₄ nanoplatform loaded with both lactate oxidase and the mitochondrial uncoupling agent carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The acid-responsive release of Fe²⁺/Fe³⁺ initiates the Fenton reaction, while lactate oxidase converts lactate in the tumor microenvironment into H₂O₂ as a self-supplying substrate. CCCP amplifies ROS leakage by disrupting the mitochondrial membrane potential. The synergy of these three factors triggers mitochondrial dysfunction and endoplasmic reticulum stress, blocks autophagic flux, and ultimately drives an atypical death pathway characterized by extensive cytoplasmic vacuolization—pyroptosis. This study is the first to shift iron-based nanomedicine CDT from the classical apoptotic pathway toward pyroptosis, and to stimulate strong anti-tumor immunity in combination with anti-PD-L1, thereby significantly inhibiting the growth of primary and distant metastases.¹²⁹ Moreover, Ding et al designed a mitochondria-targeted covalent organic framework nanoprodrug, COF-31@P. By releasing Fenton-like copper complexes and the catalase inhibitor 3-aminotriazole (3-AT) via GSH-responsive disulfide bonds, this system blocks H₂O₂ degradation while targeting mitochondria. This achieves efficient accumulation of ·OH in the cellular energy center, as well as a functional closed loop from ROS amplification to mitochondrial damage and cell death.¹³⁰ Owing to the unique anatomical structure of the lungs, the CLDCu nanodevice designed for inhalable delivery achieved a drug accumulation rate of 63.6% in lung lesions through its Cu²⁺-chitosan shell and LMWH-TOS core structure—a rate 56.5 times higher than that achieved with intravenous injection. After inhalation administration, the acidic microenvironment triggers the synergistic release of Cu²⁺ and disulfiram to generate CuET, which blocks the Cu²⁺ efflux protein ATP7B and forms toxic Cu²⁺ species, thereby significantly enhancing the cuproptosis effect. Meanwhile, the release of chitosan synergizes with cuproptosis-induced activation of the STING pathway, significantly enhancing dendritic cell maturation and both innate and adaptive immune responses.⁸³ Thus, the frontier of CDT in lung cancer has advanced beyond simple catalytic ROS production and evolved into systematic reshaping of tumor cell death modalities. This approach is no longer limited to passive oxidative damage; instead, it precisely regulates multiple programmed death pathways, synchronously optimizes the tumor microenvironment, and overcomes drug resistance. By moving from superficial killing to deep mechanistic intervention, it opens a new practical path toward efficient and precise anti-tumor treatment.

PDT: Dominant Paradigm of Photosensitive Targeting for Superficial Solid Tumors

Among the four major NDT modalities covered in this review, PDT is the oldest and most clinically established. ROS generation in PDT occurs mainly via two pathways: Type I reactions produce free radicals—such as superoxide (O₂•⁻) and ·OH—through electron or hydrogen atom transfer from substrates; Type II reactions generate ¹O₂ through energy transfer from the triplet-state photosensitizer to ground-state molecular oxygen. As a low-risk, highly selective ablative therapy, PDT has been successfully integrated into modern multidisciplinary comprehensive treatment systems for lung cancer due to its advantages, including minimal invasiveness, limited tissue damage under non-ionizing radiation, no cross-resistance, and the ability to be repeated over short intervals.¹³¹ In clinical practice, PDT is particularly suitable for carcinoma in situ (CIS) and superficial T1-stage lesions with a diameter of ≤1 cm. By introducing a 630 nm laser fiber via bronchoscopy, the photosensitizer accumulated in tumor tissue is activated at an irradiation dose of 200–400 J/cm² to generate ROS and induce tumor cell apoptosis or necrosis, while maximizing preservation of airway structure and lung function.¹³² Therefore, PDT is particularly suitable for early-stage lung cancer patients who cannot tolerate surgical resection due to advanced age, insufficient cardiopulmonary reserve, or comorbidities, as well as for palliative treatment of obstructive airway lesions caused by advanced central tumors.¹³³ Meanwhile, several traditional photosensitizers have been approved globally for lung cancer diagnosis. However, photosensitizers used in clinical practice often have a single mechanism of action and fail to achieve significant therapeutic effects.¹³⁴ Currently, the emergence of nanomaterials greatly enhances the therapeutic efficacy of PDT in lung cancer treatment (Table 2).

Table 2.

Approved Photosensitizer Commonly Used in Lung Cancer Treatment

PS	Active Ingredients	WV(nm)	Major Characteristics	Indications	Ref.
Photofrin	Porfimer sodium (HpD derivative, mixture of porphyrin oligomers)	630	Selective retention of tumors, significant skin phototoxicity (avoiding light for 4–6 weeks), low molar extinction coefficient (1170 M ⁻1 cm ⁻1)	Advanced lung cancer, early lung cancer, esophageal cancer, bladder cancer, Barrett’s advanced esophageal neoplasia	[135]
Laserphyrin	Talaporfin Sodium (NPe6, Mono-L-Aspartic Acid Hypochlorin e6)	664	Chlorophyll aspartic acid conjugate has high water solubility, high singlet oxygen quantum yield, and excellent tumor selectivity. Normal tissue clearance is fast, skin phototoxicity is low, and the light avoidance period is short (about 2 weeks)	Early central lung squamous cell carcinoma (approved by Japan PMDA in 2003), malignant brain tumors, recurrent esophageal cancer	[136]
DHA@MIL-101	Dihydroartemisinin + Fe-MOF	N/A (CDT)	Acidic TME responds to degradation, Fe 2 ⁺ catalyzes Fenton reaction, DHA synergistically exhausts GSH, inhibits GPX4, ultimately leading to iron death and apoptosis	NSCLC	[122]
Curcumin NiMs	Curcumin-loaded PLGA nanoparticles in microparticles	430–470	Inhalable Nano in Microparticles with FPF of 64.94% and MMAD of 3.02 μ m, compatible with pulmonary surfactant, LED activation for selective killing	Lung cancer	[137]
PPa-PLGA NPs	Pyropheophorbide-a @ PVA/TPGS-PLGA nanoparticles	670	Dual emulsifier stability, hydrophobic PPa water-soluble conversion, photodynamic ablation of planktonic lung cancer cells with low light bleaching	Lung cancer	[90]

In lung cancer treatment, the anti-tumor effect of PDT is not limited to the direct cytotoxicity mediated by ROS generated after photosensitizer activation; rather, it operates through a multi-level mechanism. First, ROS can induce various cell death modes in lung cancer cells, including apoptosis, necrosis, and ferroptosis. Second, PDT can damage tumor-associated blood vessels, reduce tumor blood supply, and exacerbate local metabolic stress. Third, and most importantly, PDT-induced immunogenic cell death promotes tumor antigen release, dendritic cell maturation, and effector T cell infiltration, thereby helping to transform the immunosuppressive “cold” microenvironment of lung cancer into an immunostimulatory “hot” microenvironment (Figure 7).¹³⁸

Figure 7.

Multilevel antitumor mechanisms of photodynamic therapy (PDT) in lung cancer. Upon light activation, photosensitizers generate reactive oxygen species (ROS), particularly singlet oxygen, which exert direct cytotoxic effects on tumor cells and induce multiple forms of cell death, including apoptosis, necrosis, and ferroptosis. PDT also damages tumor-associated vasculature, leading to vascular occlusion, reduced tumor perfusion, and enhanced local metabolic stress. In parallel, PDT-induced immunogenic cell death promotes tumor antigen release, inflammatory responses, dendritic cell maturation, and effector T-cell infiltration, thereby activating antitumor immunity and facilitating the conversion of an immunosuppressive “cold” tumor microenvironment into an immunostimulatory “hot” microenvironment. Adapted from Correia JH, Rodrigues JA, Pimenta S, Dong T, Yang Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics. Copyright © 2021 by Correia et al.¹³⁹

PDT utilizes photoactivated photosensitizers (PS) to generate cytotoxic ROS, targeting supportive stromal cells within the TME that promote tumor growth. This modality not only reduces tumor burden but also shifts the TME toward a state that is detrimental to tumor progression. Mitochondria are among the core targets of ROS attack in PDT. As the main source of intracellular ROS and the central regulator of redox balance, mitochondria are highly sensitive to PDT-induced oxidative stress. In a study by Zheng et al, the novel photosensitizer DTPP-mediated PDT significantly increased ROS and NO levels, decreased GSH content and mitochondrial membrane potential in LA795 lung cancer cells, upregulated Bax and cytochrome c expression, inhibited Bcl-2 expression, and induced cascade activation of caspase-9 and caspase-3, ultimately triggering apoptosis via the mitochondrial pathway.¹⁴⁰ Similarly, the NO-releasing photosensitizer ZnPc-2NO reported by Xu et al has been shown to reduce cellular oxygen consumption, inhibit ATP production, and alter mitochondrial membrane potential (MMP) in A549 lung cancer cells. It retains the ability to generate ROS and induce cytotoxicity under hypoxic conditions.¹⁴¹ PDT can directly damage endothelial cells within the TME and subsequently interfere with the blood supply to cancer cells. This makes PDT a precise, minimally invasive, and synergistic anti-tumor strategy, particularly suitable for solid tumors with abundant blood supply. A study found that L-PD upregulates expression of the tumor endothelial cell adhesion molecule E-selectin by activating the NF-κB signaling pathway, thereby significantly enhancing intratumoral infiltration of CD3⁺CD8⁺ granzyme B⁺ cytotoxic T lymphocytes in NSCLC and malignant pleural mesothelioma models, effectively inhibiting tumor progression.¹⁴² Guan et al reported that PDT-induced tumor vascular disruption promotes dendritic cell maturation, followed by secretion of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α), thereby activating T lymphocytes via upregulation of CD4⁺ and CD8⁺ T cell differentiation clusters. In addition, downregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9 also reduced the tumor metastasis rate.¹⁴³ The vascular disruptive effect of PDT has also been successfully applied to locally enhance chemotherapy drug delivery. Wang et al found that low-dose Visudyne-mediated PDT significantly enhances the uptake of liposomal doxorubicin in various lung tumor models, including pulmonary sarcoma, mesothelioma, and adenocarcinoma. The degree of enhancement correlates with the basal vascular density of the tumor but has no significant effect on normal lung tissue.¹⁴⁴ When immune surveillance is impaired, tumor cells can continue to proliferate and form malignant tumors.¹⁴⁵ What’s more, tumor cells can evade immune system barriers through various mechanisms, which is the primary reason for the low clinical efficacy of most anti-tumor treatments.¹⁴⁶ PDT induces a strong acute inflammatory response at the tumor site due to photodamage to the tumor and its microenvironment.¹⁴⁷ Subsequently, it stimulates the immune system and leads to infiltration of host innate immune cells, which clear damaged cells in the treatment area,^147,148 reverse immune suppression, achieve local tumor control, and provide systemic inhibition for long-term anti-cancer metastasis prevention. Lan et al¹⁴⁹ designed a new nanophotosensitizer, Fe-TBP, which exhibited a release efficiency of 90% under hypoxic conditions after 2 hours of irradiation. This metal–organic framework (MOF) effectively stimulates the ICD effect in tumors, thereby inducing cytotoxic T cell infiltration and generating anti-tumor immune responses.^150,151 The NTR-activated photosensitizer NO₂/BDP-BT developed by Chen et al using an “integrated” molecular design strategy combines tumor mitochondrial targeting, hypoxia-responsive fluorescence enhancement, and in situ generation of type I/II ROS. This photosensitizer achieved a tumor inhibition rate of 93.2% in a lung cancer mouse model and significantly enhanced the anti-tumor immune response through the synergistic effect of the mitochondrial apoptosis pathway and ICD.¹⁵² Wang et al reviewed nanocarrier‑based photodynamic therapy for lung cancer. Targeting ligand modification improves photosensitizer accumulation and reduces self‑quenching. Combination with immune checkpoint inhibitors and chemotherapeutics enhances antitumor efficacy and inhibits metastasis.¹⁵³ Chriqui et al found that low‑dose PDT activates the NF‑κB pathway. It upregulates vascular E‑selectin and enhances cytotoxic T lymphocyte infiltration in NSCLC and mesothelioma. This effectively inhibits tumor progression.¹⁴²

However, the clinical utility of traditional PDT is limited by several issues, including poor water solubility of photosensitizers, photobleaching, and skin phototoxicity. Additionally, the rapid attenuation and scattering of light within the lung parenchyma further restrict its applicability to deep-seated lesions. In addition, oxygen consumption and vascular damage during PDT may exacerbate tumor hypoxia, potentially shifting its effects from pro-apoptotic to anti-apoptotic.^154,155 These challenges have positioned nanotechnology as a key driver in overcoming the limitations of PDT. The core design of nano-PDT platforms involves multiple strategies—including liposomes, polymer micelles, metal nanomaterials, and carbon-based nanocarriers—to systematically enhance photosensitizer solubility, tumor enrichment efficiency, and cellular uptake.¹⁵⁶ Liposomes, owing to their phospholipid bilayer structure, can effectively encapsulate hydrophobic photosensitizers, protecting them from physiological degradation while achieving passive tumor targeting via the enhanced permeability and retention (EPR) effect.¹⁵⁷ Chen et al constructed a hybrid biomimetic nanoparticle, HLP@SiTGF-β1, which uses a ZIF-8 core to load TGF-β1-targeted siRNA. The outer layer is encapsulated with a hybrid membrane formed by fusing liposomes with the Lewis lung cancer cell membrane. Through homologous targeting, this nanoparticle achieves effective dual inhibition of both primary lung cancer lesions and brain metastases.¹⁵⁸ A key advantage of liposomes is their compatibility with nebulized inhalation for non-invasive pulmonary delivery. A study encapsulated two near-infrared photosensitizers—indocyanine green (ICG) and DiR—in liposomes based on archaeal tetraether lipids (TEL). After nebulization and delivery to A549 cells, the IC₅₀ of DiR-loaded liposomes under near-infrared (NIR) irradiation was only 9.65 µg/mL, and the liposomes maintained excellent colloidal stability both before and after nebulization.¹⁵⁹ Polymeric nanoparticles can achieve intelligent controlled release of photosensitizers.¹⁵⁷ Zeng et al designed a 660 nm-excited polylactic acid (PLA)-based nanoparticle photosensitizer carrier for the co-delivery of osimertinib and hematoporphyrin monomethyl ether (HMME). This polymeric system achieved synergistic enhancement of PDT and EGFR-targeted therapy in a subcutaneous tumor model of HCC827 non-small cell lung cancer harboring an EGFR mutation.⁹¹ Meanwhile, Pramual et al used PVA and TPGS as dual emulsifiers to stabilize PLGA nanoparticles and encapsulate pyropheophorbide-a (PPa), thereby transforming the water solubility challenge of PPa into a delivery advantage.⁹⁰ Gold nanoparticles (AuNPs) have become another research focus in lung cancer PDT owing to their unique surface plasmon resonance (SPR) effect, favorable biocompatibility, and customizable surface chemistry. AuNPs can compensate for the poor water solubility of traditional photosensitizers by improving their dispersion stability in hydrophobic environments, while their SPR effect enhances local light absorption efficiency and amplifies ROS production. A laboratory study by Crous and Abrahamse combined PDT with AuNPs for the targeted ablation of lung cancer stem cells (CSCs). The results showed that AuNPs-mediated nano-PDT induced specific cell death in A549 lung cancer stem cells, while significantly reducing stem cell migration and proliferation activity, but had minimal effect on normal lung cells.¹⁶⁰

In the context of lung cancer PDT, carbon nanotubes (CNTs) not only efficiently load photosensitizers via π–π stacking or hydrophobic interactions—thereby overcoming the delivery bottlenecks of traditional photosensitizers, such as poor water solubility and self-quenching—but also promote nanocomposite penetration through cell membranes to achieve efficient intracellular delivery.¹⁶¹ Compared with CNTs, graphene quantum dots (GQDs) represent another important class of carbon-based nanomaterials, known for their smaller size, tunable photoluminescence properties, and low cytotoxicity. For example, Zhou et al set up a multimodal synergistic therapy nanoplatform based on graphene oxide (GO), designated GO-CisPt-Ce6@MnO₂. Its core function is to address tumor hypoxia and redox imbalance while simultaneously enhancing the efficacy of chemotherapy and PDT. Carboxylated GO nanosheets serve as multifunctional carriers for loading cisplatin (CisPt) and the photosensitizer Ce6, followed by in-situ growth of MnO₂. Within the tumor microenvironment, MnO₂ decomposes endogenous H₂O₂ to generate O₂, alleviates tumor hypoxia, improves oxygen-dependent PDT efficacy, and depletes intracellular GSH to amplify oxidative stress. After irradiation, Ce6-mediated PDT generates cytotoxic ROS—including ¹O₂ and ·OH—while the released CisPt exerts chemotherapeutic effects, thereby achieving enhanced synergistic anti-tumor therapy. To overcome monotherapy resistance, PDT is often combined with other modalities, including photothermal therapy (PTT), chemotherapy, and immunotherapy. These combinations leverage complementary mechanisms to enhance efficacy and reduce toxicity and side effects at low doses. Apart from that, these combinations integrate active targeting, stimulus-responsive drug release, and multimodal combination therapy. This review summarizes the nanodesigns that have been incorporated into lung cancer PDT strategies (Table 3).

Table 3.

Summary of Nanomaterial Designs That Have Been Incorporated Into Multimodal Lung Cancer PDT Strategies

Nanoparticles	Targeting Ligand	Responsive Mechanisms	Combination Therapy	Tumor Cells	Ref.
TBPPN (GSH responsive AIE photosensitizer)	— (passive EPR)	GSH responsive dinitrobenzene cleavage, aggregation induced luminescence (AIE) activation	PDT+GSH depletion	NSCLC	[162]
MnO2@Ce6-MSCs	Mesenchymal stem cell membrane	MnO 2 catalyzes H 2 O 2 to produce O 2 and alleviates hypoxia; 633 nm laser activated Ce6	PDT+hypoxia relief	LLC lung cancer cells	[163]
GNPs@PEG/Ce6-PD-L1 peptide	PD-L1	660 nm laser activated Ce6, surface plasmon enhanced PTT of GNPs	PDT+PTT+immune checkpoint targeting	NSCLC	[164]
IPC nanodrugs (Ce6-Iridium-PVP)	— (Passive EPR, self-assembly)	630 nm laser activated Ce6, iridium ion catalyzed depletion of GSH, simulating catalase production of O 2	PDT+hypoxia relief+immune regulation	Lung cancer	[89]
ROS-responsive biomimetic nano-platform	— (Biomimetic nano platform)	ROS responsive drug release, photothermal enhanced PDT, and immune regulation	PDT+PTT+Immunotherapy	Lung cancer	[165]
Gefitinib-PLGA NPs + 5-ALA	— (Local deposition in the lungs)	630 nm laser activation of 5-ALA metabolite PpIX, synergistic with gefitinib chemotherapy	PDT+chemotherapy (CPDT)+anti angiogenesis	Lung cancer	[166]

Besides, at the level of active targeting, ligand coupling strategies targeting receptors that are highly expressed in lung cancer have demonstrated significant advantages. The EGFR is frequently overexpressed in lung adenocarcinoma. Coupling of anti-EGFR monoclonal antibodies or nanobodies with nanoparticles enables precise delivery of photosensitizers to EGFR-positive tumor cells.¹⁵⁶ Hyaluronic acid (HA) serves as a natural ligand for CD44 receptors, and HA-modified nanocarriers enhance tumor cell uptake via receptor-mediated endocytosis. Researchers have constructed a UiO-SNO@CuS/HA nanocomposite, in which HA confers CD44 targeting ability, CuS generates a photothermal effect under 1064 nm laser irradiation and simultaneously triggers the release of NO and the dissolution of Cu²⁺. The generated Cu⁺ then generates ·OH via a Fenton-like reaction, achieving triple synergistic therapy combining photothermal, gas, and chemodynamic effects.¹⁶⁷ Furthermore, the HA targeting strategy has also been extended to combined chemotherapy and photodynamic therapy. Wang et al developed a GEM@HA-(HAP/PSI) nanoplatform, which uses a hydroxyapatite/poly(succinimide) core for drug loading and is surface-coupled with HA to achieve CD44 targeting. In an A549 xenograft model, this platform demonstrated significantly enhanced tumor growth inhibition and improved safety compared with free gemcitabine.¹⁶⁸ From simple cellular uptake enhancement to multimodal therapy synergy and immune microenvironment remodeling, active targeting is driving the functional evolution of PDT from “precise killing” toward “precise regulation”, thereby providing key technical support for overcoming drug resistance and immune evasion in lung cancer treatment.

RDT: Key Pathway for Enhancing Radiotherapy Efficacy in Deep-Seated Tumors

Lung cancer is one of the solid tumors most frequently treated with radiation therapy worldwide. From curative to palliative settings, and from early to advanced stages, lung cancer treatment heavily relies on radiotherapy, which provides a natural foundation for the integration and clinical translation of RDT.^169–171 For locally advanced, unresectable NSCLC, concurrent chemoradiotherapy combined with immune consolidation therapy has become the current standard treatment paradigm.^169,170 For patients with oligometastasis or oligoprogression, stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has been shown to significantly prolong progression-free survival and reshape systemic treatment paradigms.¹⁷² The extensive reliance on radiotherapy throughout the entire disease course means that RDT can be directly integrated into existing frameworks. These include SBRT, intensity modulated radiotherapy (IMRT), and concurrent chemoradiotherapy. No independent energy delivery system is needed. Using widely available X-ray or gamma ray-activated nanoplatforms, ROS can be generated, which naturally meets the anatomical treatment requirements of deep lung cancer lesions.¹⁷³ In recent years, various nanosystems have successfully validated this concept in lung cancer models. For example, Cai et al reported two-dimensional metal–organic framework nanosheets (Hf-TCP NSs) based on hafnium porphyrin. Their high-Z Hf₆ clusters efficiently generate ¹O₂ by transferring energy to porphyrin ligands under X-ray irradiation. These nanosheets exhibited strong radiodynamic killing effects in both subcutaneous and orthotopic models of NSCLC, reducing tumor volume by over 80%.¹⁷⁴ Meanwhile, Zhong et al constructed monodisperse NaCeF₄:Gd,Tb nanoscintillators loaded with the photosensitizer Ce6. These scintillators convert X-rays into visible light to activate Ce6, achieving ROS burst and growth inhibition in deep lung cancer lesions.¹⁷⁵ RDT operates on a distinct mechanism compared with conventional nanoradiosensitization. Typical high-Z nanosensitizers like nanoparticles based on gold, hafnium and gadolinium boost local physical dose deposition mainly via the photoelectric effect, Compton scattering and Auger electron emission. The core principle behind this approach lies in amplifying energy deposition.^176,177 RDT functions by amplifying reactive oxygen species on nanoplatforms under radiation exposure. This approach produces large quantities of ROS using radiation-activated photosensitizers or nanomaterials and belongs to the category of chemical sensitization.^87,173 There is an overlap between the two mechanisms in terms of energy conversion: high-Z elements can both physically enhance radiosensitivity and act as catalysts to participate in ROS generation. Nonetheless, the starting points and biological endpoints of the two mechanisms differ. The former focuses on the advantages of physical dosimetry and enhancement of direct DNA damage, while the latter emphasizes active activation of oxidative stress pathways and chemical regulation of cell death modalities.^173,176 Therefore, classifying RDT merely as an advanced form of radiosensitization will obscure the distinctions between physical and chemical sensitization and may also lead to inappropriate positioning for its clinical application. At present, research on nanoradiosensitization for lung cancer has become relatively mature, laying a solid preclinical and early clinical foundation for the combined application of RDT. Numerous studies have confirmed that high-Z nanoparticles achieve radiosensitization by amplifying oxidative stress, enhancing DNA double-strand breaks, and activating immune responses. For example, Chen et al used the human serum albumin-manganese dioxide nanoplatform (HSA-MnO₂) to catalyze the production of O₂ from H₂O₂ in tumors, thereby overcoming hypoxia. Simultaneously, the released Mn²⁺ was converted into ·OH via a radiation-mediated Fenton-like reaction, thereby amplifying the oxidative damage cascade. The radiotherapy efficacy in NSCLC tumor-bearing mice was improved nearly threefold.¹⁷⁸ Another research team constructed albumin-modified gold nanoparticles (Alb-GNPs) to enhance lung cancer radiotherapy. These nanoparticles utilize the high atomic number properties of gold to enhance local energy deposition from X-rays, while albumin modification improves their biocompatibility, stability, and tumor enrichment ability. This platform showed significant radiosensitizing effects in the A549 non-small cell lung cancer model. This study suggests that high-Z gold nanomaterials modified with albumin can serve as a low toxicity platform for lung cancer RDT and radiosensitization. The cascade involving tumor enrichment, radiation energy deposition and amplified DNA damage enables precise radiotherapy enhancement for deep-seated lung cancer lesions (Figure 8).⁸⁸ Gold nanoparticles carrying SP1 small interfering RNA (AuNPs-si-SP1) increase the sensitization enhancement ratio (SER) of A549 cells to 2.13 by downregulating SP1 expression, upregulating granzyme B (GZMB), and inducing G2/M phase arrest, thereby achieving a synergistic effect of gene silencing and physical sensitization.¹⁷⁹ Furthermore, recent studies have confirmed that silver nanoparticles induce ROS bursts, mitochondrial dysfunction, and inhibition of DNA damage repair in A549 and cisplatin-resistant A549/DDP cells, thereby overcoming chemotherapy resistance and enhancing radiosensitivity.¹⁸⁰ The study of gadolinium-based nanoparticles (AGuIX) provides another important dimension for lung cancer radiosensitization. Du et al confirmed that AGuIX significantly exacerbates radiation-induced DNA double-strand breaks (DSBs) and inhibits DNA damage repair in H1299 NSCLC cells by emitting low-energy photoelectrons and interacting with Auger electrons, thereby effectively inhibiting tumor growth in a mouse xenograft model.¹⁸¹ Bismuth-based nanoparticles (BiNPs), owing to their extremely high X-ray absorption coefficient (atomic number Z = 83), emit a cascade of photoelectrons, Auger electrons, and Compton electrons upon irradiation. Through water radiolysis, abundant ·OH are generated, leading to mitochondrial dysfunction and irreversible oxidative damage, including DNA double-strand breaks.¹⁸² In terms of immune regulation, the cRGD peptide-targeted AGuIX-Bi nanoparticles (AGuIX-Bi-cRGD) constructed by the Lux/Reinforcement team not only achieve physical sensitization by enhancing DNA double-strand breaks in Lewis lung cancer models but also induce overexpression of the immunogenic cell death marker HMGB1 and significantly increase the density of tumor-infiltrating CD3⁺CD8⁺ cytotoxic T cells.¹⁷² In the interdisciplinary field combining RDT and CDT, pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) constructed by Li et al dissociate and release Fe²⁺ in the acidic tumor microenvironment following local pulmonary delivery. Following a single X-ray irradiation, mitochondrial superoxide anions are converted into H₂O₂ by superoxide dismutase, which then generates highly toxic ·OH via the Fenton reaction, ultimately driving lipid peroxidation and synchronously inducing apoptosis and ferroptosis. This strategy cleverly integrates the triple mechanisms of RDT, CDT, and ferroptosis into a single nanoplatform, not only breaking through the efficacy bottleneck of monotherapy but also highlighting the unique advantages of local delivery in reducing pulmonary systemic toxicity.⁸⁶ Clark et al, in a preclinical study, confirmed that RDT combined with 5-ALA significantly delayed metastatic progression and improved survival outcomes in a small-cell lung cancer metastasis model; both low-dose (0.1 Gy) and high-dose (2 Gy) RDT groups showed superior survival benefits over conventional radiotherapy (p < 0.004), suggesting that RDT holds promise as a systemic therapeutic strategy for metastatic lung cancer.¹⁸³ Therefore, RDT for lung cancer is most appropriately defined as radiotherapy combined with nanodynamic therapy. This approach applies nanodynamic techniques to intensify radiation-triggered oxidative stress, DNA damage and immunogenic cell death. We should not regard it as a fully developed treatment that can independently address the challenges posed by deep-seated lesions. Integrating RDT into current SBRT and chemoradiotherapy regimens and remodeling the tumor microenvironment via physical sensitization alongside chemical ROS amplification can drive lung cancer radiotherapy forward. This evolution moves the treatment focus beyond local dose escalation toward systematic reprogramming of cell death pathways and immune modulation.

Figure 8.

Albumin-modified gold nanoparticles enhance radiotherapy-induced oxidative DNA damage in lung cancer. This figure illustrates the preparation process of albumin-modified gold nanoparticles (Alb-GNPs) and their radiosensitization mechanism. First, gold nanoparticles (GNPs) were synthesized using the Turkevich method, with HAuCl₄ as the gold source and sodium citrate as the reducing agent. Subsequently, Alb-GNPs were formed by coating the GNPs with human serum albumin (HSA). After intravenous injection, Alb-GNPs become enriched in lung cancer tissues and promote tumor cell uptake through SPARC-mediated interactions. Under X-ray irradiation, gold nanoparticles enhance local energy deposition and release secondary electrons, thereby amplifying ROS generation and γH2AX-related DNA damage. This increases the sensitivity of lung cancer cells to radiotherapy and inhibits tumor growth. Adapted from Chen Y, Liu S, Liao Y, et al Albumin-Modified Gold Nanoparticles as Novel Radiosensitizers for Enhancing Lung Cancer Radiotherapy. Int J Nanomedicine. 2023;18:1949–1964. Copyright © 2023 by Chen et al¹⁸³.

Nanodynamics Synergistic Precise Combination Therapy for Lung Cancer

Although NDT alone can induce tumor cell death, the high heterogeneity, complex TME, and multidrug resistance mechanisms of lung cancer often limit its therapeutic efficacy. In recent years, combination strategies based on molecular typing and anatomical features have become a key approach to overcoming these bottlenecks. On one hand, ROS generated by NDT can reshape tumor redox homeostasis and overcome drug resistance synergistically with targeted agents. On the other hand, NDT-induced ICD can provide a “hot start” signal for immunotherapy. More importantly, as the lungs are directly connected to the respiratory tract, the unique anatomical structure of lung cancer provides unparalleled pharmacokinetic advantages for inhalation and local pulmonary delivery compared with other solid tumors. This enables spatial and temporal coupling of NDT with exogenous activation (eg, ultrasound, X-rays) or endogenous catalysis (eg, Fenton reactions triggered by the acidic microenvironment). This review summarizes NDT combination therapy systems constructed around three dimensions: EGFR molecular typing, anti-angiogenic pathways, and local pulmonary delivery. This framework not only aligns with the biological essence of lung cancer but also represents a necessary pathway to advance NDT from “proof of concept” to “clinical translation”. We have summarized several combination therapies (Table 4).

Table 4.

Nanodynamic Therapy-Based Precision Combination Strategies for Lung Cancer

Combination Strategy	Representative Nanoplatform	NDT Modality	Lung Cancer Model/Indication	Precision or Synergistic Component	Main Therapeutic Mechanism	Relevance to Precision Lung Cancer Therapy	Ref.
NDT + EGFR-TKI	Ce6–erlotinib carrier-free nanoparticles (Ce6-Erl NPs/EC-NPs)	SDT + targeted therapy	NSCLC	Erlotinib-mediated EGFR inhibition	Ultrasound activates Ce6 to generate ROS/1O2, while erlotinib suppresses EGFR/PI3K/AKT and MAPK signaling, jointly inducing mitochondrial dysfunction and apoptosis.	Provides a dual “signal blockade + oxidative killing” strategy for EGFR-driven NSCLC.	[78]
NDT + EGFR-TKI resistance reversal	cRGD-targeted gold-based nanoparticles	Low-temperature PTT + SDT	EGFR-TKI-resistant NSCLC	cRGD targeting and photothermal sensitization	Gold-based nanoparticles enhance mild hyperthermia and SDT-induced ROS, helping bypass adaptive resistance to EGFR-TKIs.	Directly addresses acquired EGFR-TKI resistance, a major clinical barrier in advanced NSCLC.	[81]
NDT + osimertinib-based precision therapy	Osimertinib–copper–ICG self-assembled nanomedicine	Chemo-photo-CDT + cuproptosis	NSCLC	Osimertinib targeting EGFR-mutant tumor cells	Osimertinib blocks EGFR signaling, copper catalyzes Fenton-like ROS production and promotes cuproptosis, while ICG enables photoactivation.	Integrates molecular targeting, metal-ion catalysis, photoactivation, and cuproptosis for EGFR-mutant or TKI-resistant NSCLC.	[85]
NDT + anti-angiogenic therapy	Biomimetic anlotinib-loaded FePc-silicate nanoparticles	SDT + anti-angiogenesis + immunotherapy	NSCLC	Anlotinib-mediated VEGFR2/JAK2/STAT3 inhibition	FePc-silicate produces ROS under ultrasound; anlotinib inhibits angiogenic signaling and downregulates intracellular PD-L1, enhancing CD4⁺/CD8⁺ T-cell infiltration.	Combines vascular normalization/anti-angiogenesis, SDT, and immune activation in NSCLC.	[80]
NDT + chemotherapy	Cationic liposomal hydroxycamptothecin + 5-ALA	Chemo-SDT	Metastatic lung cancer	Pulmonary delivery of chemotherapeutic drug and endogenous sonosensitizer precursor	5-ALA is metabolized into PpIX, which generates ROS under ultrasound; hydroxycamptothecin provides chemotherapy-induced DNA damage.	Demonstrates local lung delivery of chemo-SDT for metastatic lung cancer with reduced systemic exposure.	[82]
Inhaled NDT + chemo-sonodynamic therapy	Size-transformable pulmonary nanoparticles	SDT + chemotherapy	Lung cancer	Size transformation for tumor accumulation and deep penetration	Larger nanoparticles improve lung retention; after tumor deposition, smaller inner particles penetrate deeper and release chemotherapeutic drug plus sonosensitizer for ultrasound-triggered ROS generation.	Represents a “large-size delivery–small-size penetration–external activation”paradigm for lung-localized NDT.	[184]
NDT + radiation therapy	Pulmonary theranostic nanoclusters	CDT + radiation-enhanced ferroptosis	Lung cancer	Pulmonary delivery and imaging-guided treatment	Acidic TME triggers iron release and Fenton reaction; radiation increases H2O2/ROS production, jointly inducing ferroptosis and tumor suppression.	Combines local lung delivery, diagnostic guidance, CDT, radiotherapy, and ferroptosis.	[86]
NDT + radiotherapy sensitization	Albumin-modified gold nanoparticles	Radiodynamic/radiosensitization therapy	Lung cancer	Albumin modification for improved biocompatibility and tumor interaction	Gold nanoparticles enhance local radiation energy deposition and ROS-mediated DNA damage, thereby improving radiotherapy efficacy.	Uses clinically established radiotherapy as an external trigger to amplify nanodynamic oxidative damage.	[88]
NDT + chemotherapy + radiotherapy	Doxorubicin-conjugated polymeric nanoparticles + 5-ALA	RDT/radiotherapy sensitization + chemotherapy	Lung cancer	Polymeric delivery of doxorubicin and 5-ALA	5-ALA-mediated porphyrin accumulation enhances radiation-induced ROS production, while doxorubicin contributes chemotherapy-induced cytotoxicity.	Provides a multimodal chemo-radiodynamic strategy for lung cancer.	[87]
NDT + ferroptosis	Dihydroartemisinin-assisted Ce6 system	PDT + ferroptosis	Lung cancer	DHA-mediated GPX4 inhibition	DHA inhibits GPX4 and increases lipid peroxidation, thereby sensitizing lung cancer cells to Ce6-mediated PDT.	Links PDT-induced ROS generation with ferroptosis-based death-pathway reprogramming.	[92]
Inhaled NDT + ferroptosis	Nebulized iron-based nanoparticles	Iron-based CDT/ferroptosis	Early orthotopic lung cancer	Nebulized local delivery and macrophage-regulated ferroptosis	Iron-based nanoparticles promote ferroptosis of cancer stem-like cells and remodel the immune microenvironment in orthotopic lung cancer.	Highlights inhaled ferroptosis-inducing nanomedicine for early lung-localized lesions.	[185]
NDT + NRF2 modulation + ferroptosis	NRF2 nano-modulator	Ferroptosis-associated nanotherapy	Lung cancer	NRF2 redox pathway modulation	NRF2 inhibition weakens antioxidant defense, promotes ferroptosis, and induces an immunostimulatory tumor microenvironment.	Targets the oxidative stress defense axis, especially relevant to redox-adapted or therapy-resistant lung cancer.	[186]
NDT + cuproptosis + immunotherapy	CLDCu inhalable nanoparticles	CDT + cuproptosis + cGAS–STING activation	Lung metastasis	Acid-responsive inhalable Cu2⁺/disulfiram release	Acidic TME triggers Cu2⁺ and disulfiram release to form CuET; copper accumulation induces cuproptosis and activates cGAS–STING-mediated antitumor immunity.	Strongly supports lung-localized precision therapy integrating metal-ion death and innate immune activation.	[83]
NDT + photoimmunotherapy	Biodegradable iridium-coordinated nanodrugs	PDT + immunotherapy	Lung cancer	Iridium coordination and immune activation	Iridium-coordinated nanodrugs potentiate PDT-induced ROS generation and immunogenic cell death, thereby enhancing antitumor immune responses.	Connects PDT-mediated oxidative killing with immune remodeling in lung cancer.	[89]

Combining NDT with EGFR-TKIs: Precise Combination Therapy for Molecular Typing of Lung Cancer

EGFR mutation is one of the most clinically significant molecular subtypes in NSCLC. Although EGFR-TKIs (tyrosine kinase inhibitors) have become the standard first-line treatment for this patient population, acquired resistance and local progression have remained persistent bottlenecks restricting long-term survival.¹⁸⁷ Among resistance mechanisms to third-generation TKIs such as osimertinib, the C797S tertiary mutation is a prominent on-target alteration, occurring in 10–26% of first-line and up to 30–40% of second-line progressive patients, for which no effective targeted therapy is yet available. Notably, the resistance mechanisms of EGFR-TKIs are often closely related to the remodeling of redox homeostasis. Drug-resistant cells construct a powerful antioxidant defense barrier by upregulating NADPH oxidase (NOX) activity and glutathione synthesis. Disrupting this barrier provides a precise natural interface for NDT.¹⁸⁸ In this context, the NRF2‑KEAP1 axis serves as the central hub of this antioxidant defense. Under TKI pressure, NRF2 upregulates heme oxygenase-1 (HO‑1), glutathione S-transferases (GSTs), and SLC7A11 to expand the glutathione pool. NDT‑generated ROS dismantle this network through three interconnected pathways. First, ROS cause oxidative modification of KEAP1 cysteine residues, which impairs NRF2 ubiquitination. Second, ROS downregulate SLC7A11 via the ATF4/CHOP axis, leading to cysteine and GSH depletion. Third, ROS directly inactivate GPX4 through lipid peroxidation‑mediated covalent modification. Collectively, these actions remove the terminal antioxidant checkpoint and resensitize resistant cells, including those with the C797S mutation, to TKI‑induced apoptosis. Therefore, the ROS burst generated by NDT bypasses the compensatory activation of downstream EGFR signaling pathways, directly damages mitochondrial DNA, and induces lipid peroxidation, thereby integrating the “signal blockade” of TKIs with the “oxidative killing” of NDT. Meanwhile, TKI agents such as erlotinib themselves reduce cellular antioxidant capacity by inhibiting the EGFR/PI3K/AKT pathway, thereby creating a synergistic amplification effect of “sensitization-killing”.¹⁸⁸

In recent years, several representative studies have deeply integrated NDT with EGFR-targeting strategies. Tian et al reported a carrier-free nanoparticle (Ce6-Erl NPs) based on Ce6 and erlotinib, which achieved synergistic inhibition of SDT and the EGFR signaling pathway upon ultrasound activation. This nanoparticle utilizes Ce6 as a sonosensitizer to generate ¹O₂ under ultrasound irradiation, while erlotinib continuously blocks the downstream PI3K/AKT and MAPK pathways of EGFR, thereby synergistically inducing mitochondrial dysfunction and apoptosis. This research establishes a dual-mechanism model combining targeted inhibition and oxidative killing for the precise combination treatment of EGFR-mutant NSCLC. It also demonstrates that carrier-free approaches offer notable strengths in streamlining preparation procedures and elevating drug loading capacity.⁷⁸ Additionally, Fu et al synthesized the cationic polymer PβAE to compress DNA plasmids into a stable core, and then prepared osimertinib (OST)-loaded liposomes via the thin-film dispersion method. This core was then loaded into the aqueous cavity of the liposomes, and finally, a stem cell membrane highly expressing pulmonary surfactant protein B (SP-B) was fused onto the liposome surface. After inhalation in mice, SP-B helps the MPDOLs penetrate lung tissue and become internalized by tumor cells, releasing OST and DNA plasmids upon cellular entry. OST directly inhibits the EGFR signaling pathway to prevent tumor growth, while the DNA plasmids stimulate tumor cells to self-assemble and secrete extracellular vesicles that express RVG protein and carry IGF2BP3 siRNA, simultaneously inhibiting IGF2BP3 expression and thereby enabling targeted treatment of brain metastases. While this research centers on gene therapy instead of nanodynamic therapy, its design combining inhalation delivery and EGFR targeting offers valuable insights for the spatiotemporal integration of NDT and TKIs (Figure 9).¹⁸⁹

Figure 9.

Schematic illustration depicting the therapeutic application of MPDOLs against primary pulmonary lesions and cerebral metastases in NSCLC. Following nebulization, MPDOLs achieved effective tumor deposition and deep tissue penetration facilitated by SP-B. Upon intracellular uptake, the nanocarriers discharged osimertinib and DNA plasmids into the cytoplasm, wherein the former exerted targeted inhibition of the EGFR signaling cascade, while the latter suppressed IGF2BP3 expression and initiated the self-assembly and secretion of RVG-EXOs(si) for subsequent brain metastasis targeting. Adapted from Fu X, Shi Y, Wu H, et al Inhalable liposomal delivery of osimertinib and DNA for treating primary and metastasis lung cancer. Copyright© 2025 by Fu et al¹⁹⁶.

The cRGD-targeted gold-based nanoparticles combined with low-temperature photothermal therapy and sonodynamic therapy reported by Lv et al, although focusing on overcoming EGFR-TKI resistance rather than directly combining TKIs, also confirms the key value of oxidative stress intervention in reversing TKI resistance by blocking the TGF-β/PDLIM5/SMAD resistance pathway and inducing mitochondrial apoptosis.⁸¹ The chondroitin sulfate-based nanoparticles co-loaded with curcumin and cinnamaldehyde designed by Lee et al exhibit strong resistance reversal ability in NSCLC models resistant to paclitaxel and cisplatin by increasing intracellular ROS and depleting GSH, ultimately inhibiting GPX4 and inducing ferroptosis.¹⁹⁰ This study suggests that the combination of NDT-induced ROS burst and GSH depletion can effectively break down the antioxidant defense line of drug-resistant cells, thereby providing a transferable nanoplatform strategy for overcoming EGFR-TKI resistance. The self-assembling nanoplatform of osimertinib, copper ions, and indocyanine green (OIC NPs) reported in 2025 further expands the combined therapeutic dimension. This system integrates near-infrared light-activated photodynamic therapy, copper ion-mediated chemodynamic therapy, and osimertinib chemotherapy, achieving a tumor inhibition rate of 99.8% in NSCLC models by depleting GSH, amplifying oxidative stress, and inducing cuproptosis.⁸⁵ Collectively, these studies indicate that the combination of NDT and EGFR-TKIs has progressed from concept validation to mechanistic deepening. TKI resistance in EGFR-mutant NSCLC is essentially an adaptive remodeling of redox homeostasis, and NDT represents a precise strategy to disrupt this homeostasis.

Anti-Angiogenic Therapy Combined with NDT: Reshaping the Tumor Vascular Microenvironment to Enhance Lung Cancer Nanodynamic Therapy

Anti-angiogenic therapy has a solid clinical foundation in the comprehensive management of NSCLC. From the established role of bevacizumab combined with chemotherapy as first-line treatment for advanced non-squamous NSCLC to the widespread use of ramucirumab in multi-line therapy, anti-angiogenic drugs have become an indispensable component of systemic lung cancer treatment. They inhibit the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathway to block tumor angiogenesis and promote vascular normalization.¹⁹¹ Of particular importance is the multi-target tyrosine kinase inhibitor anlotinib, independently developed in China, which has demonstrated clear anti-tumor activity in clinical practice by simultaneously blocking angiogenesis-related receptors such as VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The ALTER0303 randomized Phase III clinical trial confirmed that anlotinib, as a third-line or later treatment, significantly prolongs median overall survival and progression-free survival in patients with advanced NSCLC. It has been approved for use in patients with advanced NSCLC who have previously received two lines of systemic chemotherapy.¹⁹² Further studies have shown that anlotinib combined with immune checkpoint inhibitors produces significant synergistic effects in advanced NSCLC, achieving a median progression-free survival (PFS) of 25.4 months, and reverses the immunosuppressive microenvironment by downregulating PD-L1 expression in vascular endothelial cells.¹⁹² This clinical evidence indicates that anti-angiogenic therapy not only directly inhibits tumor blood supply but also reshapes the tumor immune microenvironment. However, anti-angiogenic therapy alone often faces the dilemma of compensatory pathway activation and drug resistance. The ROS generated by NDT can overcome this bottleneck. For example, Liu et al constructed a biomimetic nanodrug (APSNM) loaded with iron phthalocyanine silicate (FePc silicate) and anlotinib, and modified the macrophage membrane with a PD-L1 antibody. This nanoplatform achieves a triple therapeutic effect in orthotopic lung cancer models. Anlotinib inhibits the VEGFR2/JAK2/STAT3 pathway to reduce intracellular PD-L1 expression. Membrane-bound antibodies block extracellular PD-L1 signaling. Ultrasound-activated FePc silicate produces reactive oxygen species and strengthens antitumor immunity.⁸⁰ In addition, Guo et al constructed an SPIO@SiO₂-ANB nanoplatform that combines superparamagnetic iron oxide nanoparticles (SPIOs) with a silica shell, loads anlotinib on the surface, and precisely releases the drug in the acidic tumor microenvironment via a pH-responsive release mechanism. This nanoplatform not only inhibits angiogenesis via anlotinib but also utilizes the Fenton reaction activity of iron-based materials to induce ferroptosis in tumor cells and amplify oxidative stress levels. The results demonstrated superior cytotoxicity compared with free anlotinib in A549 and H460 NSCLC cells, while also significantly inhibiting tumor growth and promoting apoptosis in an in vivo xenograft model (Figure 10).¹⁹³ The combination of NDT and anti-angiogenic treatment carries greater significance. It highlights how remodeling the tumor microenvironment acts as a key factor in combined therapeutic regimens. In the future, with advances in dynamic monitoring technology and the continued iteration of multimodal nanoplatforms, this combination strategy is expected to evolve from a synergistic approach into a new paradigm for systemic treatment of advanced NSCLC. Still, current research in this area remains extremely limited, and further studies are urgently needed.

Figure 10.

The SPIO@SiO₂-ANB nanoplatform for synergistic anti-angiogenic and ferroptosis therapy in NSCLC. (A) Preparation process of the SPIO@SiO₂-ANB nanoplatform: SPIOs were synthesized using FeCl₃·6H₂O as a precursor, modified with a SiO₂ shell, and loaded with anlotinib to form pH-responsive nanoplatforms. (B) SPIO@SiO₂-ANB accumulates at the tumor site in vivo and inhibits NSCLC tumor growth. (C) In the acidic tumor microenvironment, the platform releases anlotinib to inhibit angiogenesis, while SPIOs mediate the Fenton reaction to amplify ROS generation, downregulate GPX4, upregulate COX and xCT, induce ferroptosis, and promote lung cancer cell death. Adapted from Guo M, Xue L, Li J, Zhu M, Long H, Peng J. Heterogeneous inorganic nanomedicine delivery system loaded with anlotinib for enhanced treatment of non-small cell lung cancer (NSCLC). Colloids Surf B Biointerfaces. Copyright © 2026 by Guo et al.¹⁹³

Inhalation and Local Pulmonary Delivery Strategies for NDT in Lung Cancer

Because the lungs are directly connected to the external environment, their unique anatomical features provide unparalleled advantages for local nanomedicine delivery (Table 5). Inhalation atomization allows nanoparticles to bypass hepatic filtration and deposit directly in the bronchial epithelium and alveolar regions, thereby reducing systemic toxicity while increasing local tumor exposure.¹⁹³ The integration of local delivery and exogenous activation makes lung cancer a highly suitable candidate for combination therapy based on nanodynamic treatment. Preclinical and early clinical evidence has robustly confirmed the feasibility of this approach. Phase I clinical trials of aerosolized liposomal 9-nitrocamptothecin (9NC) showed that inhalation administration increases lung drug concentrations to 4–10 times plasma levels, with controllable systemic toxicity and observable initial tumor responses.¹⁹⁴ The phase I trial of nebulized IL-2 liposomes further confirmed that inhalation delivery can be safely implemented in outpatient settings, significantly stimulating local pulmonary immune function without notable systemic toxicity. These early clinical investigations have laid a solid foundation for the inhalation delivery of NDT nanoplatforms.¹⁹⁴

Table 5.

Applications of Inhalable NDT Nanoformulations for Lung Cancer

Inhalation Formulation	NDT/Therapeutic Mechanism	Lung Cancer Model	Key Feature and Translational Relevance	Ref.
Spray-dried inhalable Nano-in-Microparticles	PDT; LED-activated ROS generation	A549 cells	Respirable formulation; FPF 64.9%, MMAD 3.02 μm; early proof of inhalable PDT formulation	[195]
Nebulizable DHA/CaP liposomes	ROS amplification and ferroptosis; Ca2⁺-burst/ER-stress reinforcement	Orthotopic lung tumor mice	~6.8-fold higher drug accumulation in lung lesions than i.v.; couples pulmonary deposition with ferroptosis amplification	[196]
Nebulized nanocatalytic formulation	Iron-mediated nanocatalysis/ferroptosis	Early orthotopic lung cancer	TAM-mediated targeting of cancer stem-cell niches; particularly relevant to early pulmonary microlesions	[185]
Inhalable OPDEA-coated Cu-MOF	Cuproptosis + ICD + anti-PD-L1 immunotherapy	Lung metastasis model	Mucus penetration and prolonged lung retention; siPDK suppresses glycolysis/ATP7B-mediated Cu⁺ efflux	[197]
Inhalable Cu2⁺/DSF nanodevice	Cuproptosis + cGAS–STING activation	Lung metastasis model	63.6% accumulation in lung lesions and 56.5-fold higher than i.v.; links local cuproptosis with innate/adaptive immunity	[83]
Nebulized macrophage-membrane nanoreactor	RT-induced ROS/ONOO⁻ + ferroptosis	Orthotopic lung cancer	~70-fold higher pulmonary accumulation than i.v. at 12 h; 93.91% tumor inhibition in the reported model	[198]
Nebulized inhalable nanozyme	Nanozyme-driven oxidative stress + ferroptosis + immune sensitization	In situ lung cancer model	Local statin delivery; promotes DC maturation and T-cell responses with limited systemic toxicity	[75]
Inhalable transferrin-targeted nanomicelles	Lysosomal ROS amplification + ferroptosis	Lung cancer in vitro/in vivo	TfR-mediated lysosomal targeting; Fe3⁺/DHA/sorafenib jointly amplify ROS and ferroptosis	[199]

Traditional inhaled nanomedicine often focuses on local enrichment of chemotherapy drugs. In contrast, Ma et al reported a size-convertible nanocarrier loaded with small particles of approximately 28 nm to carry both chemotherapy drugs and sonosensitizers. Following intratracheal instillation, size transformation occurs within the tumor tissue, releasing the small particles to achieve deep penetration.¹⁸⁴ This strategy increased the exposure of SN38 in lung cancer lesions by 199% and simultaneously achieved a synergistic effect of sonodynamic therapy and chemotherapy upon ultrasound activation. The three-tier design featuring large-size delivery, small-size penetration and exogenous activation sets a new model for achieving precise spatiotemporal regulation of NDT within lung tissues. Meanwhile, nanostructured lipid carriers (NLCs) overcome the limitations of traditional solid lipid nanoparticles (SLNs), including low drug loading and drug efflux upon storage. As a next generation delivery system, NLCs efficiently deliver chemotherapy drugs and siRNA to the lungs via inhalation. They accurately target lung cancer cells while protecting healthy lung tissue. For example, when used in combination with intravenous docetaxel, celecoxib-loaded NLCs (CXB-NLCs) produced a 67% ± 4% reduction in tumor volume in NSCLC models, which was significantly better than any monotherapy.²⁰⁰

Ferroptosis, as a lipid peroxidation-dependent cell death modality, is highly consistent with the oxidative stress characteristics of lung cancer. The pH-sensitive SPIONCs reported by Li et al, following local pulmonary delivery, dissociate and release Fe²⁺ in the acidic tumor microenvironment, generating ·OH via the Fenton reaction while simultaneously inducing apoptosis and ferroptosis.⁸⁶ Upon a single X-ray irradiation, mitochondrial superoxide anions are converted into H₂O₂ by superoxide dismutase, further amplifying the efficiency of the Fenton reaction and achieving triple synergy of RDT, CDT, and ferroptosis. This research shows that local pulmonary delivery can produce highly toxic reactive oxygen species. The effect is realized through endogenous catalysis within the acidic microenvironment and exogenous activation induced by radiation. Apart from that, various iron-based nanoplatforms have demonstrated unique advantages in lung delivery-induced ferroptosis. The zero-valent iron nanoparticles (ZVI NPs) created by Hsieh et al promote NRF2 proteasome degradation by activating the AMPK/mTOR/GSK3β/β-TrCP axis, downregulate antioxidant genes such as GPX4 and SLC7A11, and thereby sensitize lung cancer cells to ferroptosis.¹⁸⁶ The dextran-coated iron nanoparticles (DFHC) designed by Feng et al target CD206⁺ tumor-associated macrophages and tumor stem cells following nebulization inhalation, achieving immune microenvironment reprogramming through ROS and lipid peroxidation accumulation.¹⁸⁵ In the interdisciplinary field combining photodynamic/sonodynamic therapy and ferroptosis, various nanoplatforms have also shown potential for pulmonary applications. Han et al confirmed that DHA, acting as a GPX4 inhibitor, effectively sensitizes Ce6-mediated photodynamic therapy and enhances lung cancer clearance efficiency by synergistically inducing ferroptosis.⁹² Biomimetic nanoparticles developed by Zhu et al (PIOC@CM), loaded with Fe₃O₄ as the core and the sonosensitizer Ce6, enter tumor cells through homologous targeting, generate abundant ROS upon ultrasound activation, and enhance the ferroptosis effect.²⁰¹

The ROS generated by NDT is not only a direct cytotoxic agent but also a “thermal switch” that reshapes the immune microenvironment. Recent studies have confirmed that inhalation-based nanoplatforms can effectively integrate ROS generation with immune activation. Zhu et al reported an inhalation-based nanovesicle (aPD-L1 NVs@cGAMP) co-loaded with the STING agonist 2′3′-cGAMP. After nebulization, this nanovesicle activates the STING pathway in lung tumors, enhances CAR-T cell efficacy, and induces abscopal effects.²⁰² Following nebulization inhalation, the pulmonary bioluminescence intensity of the nanovesicles increased 5.5-fold compared with the intravenous injection group. Moreover, only 2% of the free STING agonist dose was required to induce equivalent secretion levels of IFN-β, IL-2, IFN-γ, and TNF-α, while avoiding systemic inflammatory reactions.²⁰³ The combination of a nanodiamond-doxorubicin conjugate with PD-L1 checkpoint blockade therapy synergistically transforms TAMs into a tumor-killing state, redirecting macrophages to attack lung cancer cells. After encapsulating TGF-β receptor 1 inhibitors within nanoparticles on the macrophage membrane, the efficacy of checkpoint inhibitors can be significantly enhanced by preventing TAMs from acquiring the M2 phenotype, inhibiting tumor metastasis, and expanding cytotoxic T cells.¹⁹⁰ Also, inhaled immunotherapy has evolved from early cytokine delivery to more complex integration with gene therapy and cell therapy. KB707, an inhaled viral particle expressing IL-2 and IL-12, is currently undergoing phase I clinical trials in patients with advanced solid tumors. Preliminary data show that no grade 3 or higher toxicity was observed in 39 patients, and that KB707 can induce local immune responses.²⁰⁴ The biomimetic lipid nanoparticles (MPDOLs) developed by Fu et al were delivered via inhalation of osimertinib combined with an IGF2BP3 siRNA plasmid. This approach not only inhibited EGFR signaling but also triggered endogenous exosome-mediated epigenetic regulation, achieving dual inhibition of both primary lesions and brain metastases.¹⁸⁹ The inhaled delivery of IL-12 mRNA via extracellular vesicles reported by Liu et al induces local inflammation and promotes systemic anti-tumor immunity in lung cancer lesions.²⁰⁵ Recently, Sakkal et al reviewed inhalable nanoparticle systems for NSCLC therapy. Nanotechnology improves inhaled chemotherapy by enhancing drug solubility, stability, and resistance to degradation.²⁰⁰ Wu et al developed an exosome‑mimetic inhalable nanocarrier (PDSA‑HSA) for targeted delivery of disulfiram to the lungs. This provides a new strategy for integrating inhaled NDT with cuproptosis therapy.²⁰⁶ The fusion of local lung delivery and NDT essentially transforms the anatomical features of lung cancer into therapeutic advantages, achieving in-situ deposition of nanomedicine through nebulization inhalation, deep penetration and controllable activation through size conversion and intelligent response, and ultimately achieving systemic immune response through ROS release and reprogramming of death pathways. In the future, inhalable nanoplatforms loaded with sonosensitizers, radiosensitizers, STING agonists and ICB antibodies are expected to trigger a sequential immune sensitization process. This process starts with local reactive oxygen species production, followed by immunogenic cell death and antigen presentation, then STING pathway activation and ultimately systemic T cell responses. It will create a new approach to shift lung cancer treatment from localized intervention to systemic immune regulation.

Challenges and Future Research Directions

NDT is at a critical stage, transitioning from concept validation to clinical practice. In the next 3–5 years, SDT-guided deep lesion interventions, inhalable NDT platforms, ferroptosis/cuproptosis coupling strategies, and the precise combination of NDT with immunotherapy, anti-angiogenesis, and EGFR-TKIs will constitute the most valuable research frontiers. However, this field still faces several challenges. First, there are four prominent shortcomings in current research methodology. Currently, the vast majority of preclinical studies still rely on subcutaneous xenograft models, which cannot accurately simulate the airway microenvironment, respiratory mechanics, or immune landscape of orthotopic lung cancer models. This results in serious deficiencies in pharmacokinetics and efficacy prediction.²⁰⁷ The distribution of direct evidence for lung cancer treated with the four NDT modalities is extremely uneven. SDT and CDT are relatively well represented. RDT, however, has significantly fewer lung cancer specific data. Most studies rely on a single endpoint. Examples include tumor volume or cell survival rate. These studies lack long term evaluations of survival benefits, distant metastasis control, and systemic immune memory.²⁰⁸ Second, nanoplatforms face practical challenges, including poor batch-to-batch consistency during scale-up production, vague quality control metrics, and steep cost curves.²⁰⁹ This also explains why carrier free self assembled nanoparticles have gained favor in recent years. These include natural polyphenol small molecule coordination assemblies and Cu²⁺ sensitizer coordination particles. They offer one step synthesis, minimal composition, and high batch to batch reproducibility.²¹⁰ Furthermore, material safety concerns are amplified in the context of local pulmonary administration. After inhalation delivery of metal based nanoparticles (such as iron, copper, gold, and gadolinium), their alveolar capillary barrier penetration, macrophage uptake, lymphatic drainage, and long term biological retention behavior are entirely different from those observed with intravenous administration. Chronic accumulation of metal ions may induce local inflammation, fibrosis, and even genotoxicity. Nevertheless, current long-term toxicology data remain almost entirely absent.^211,212 In addition, the lack of standardization of physical activation parameters severely restricts comparability across studies and hampers clinical protocol design.

To bridge the gap between preclinical promise and clinical reality, future research directions in lung cancer NDT should be strategically stratified into three tiers based on translational readiness and timelines. The first tier, short-term clinical transformation, should prioritize the development of inhalable NDT platforms for postoperative residual lesions and locally recurrent tumors that are unsuitable for re-irradiation or repeat surgery.²¹³ This tier leverages the unique anatomical accessibility of the pulmonary system and the established safety profiles of clinically validated sonosensitizers and photosensitizers, rendering it the most pragmatic and low-risk entry point for first-in-human translational studies. The second tier, representing medium-term mechanistic innovation, should prioritize the development of multi-cell-death-coupled nanozyme systems that concurrently orchestrate ferroptosis, cuproptosis, and pyroptosis within a unified nanoplatform architecture.²¹⁴ These systems are designed to overcome resistance mechanisms by engaging multiple, non-cross-resistant death pathways simultaneously,²¹⁴ and their development requires deeper understanding of the molecular crosstalk between different PCD modalities within the lung TME. The third tier, long-term systemic immunotherapy, envisions the combination of inhalable NDT with STING agonists and immune checkpoint inhibitors to achieve robust systemic anti-tumor immunity and abscopal effects.²⁰³ This tier represents the ultimate goal of transforming lung cancer from a locally destructive disease into a systemically manageable condition, but its realization depends on resolving complex questions regarding optimal sequencing, dosing, and biomarker-driven patient selection.

To operationalize these stratified research directions, we propose a comprehensive translational roadmap comprising three sequential phases. Phase I (Formulation Optimization and GLP Toxicology) should focus on developing inhalable NDT nanoplatforms with rigorously characterized aerodynamic particle size distribution, high fine particle fraction (FPF > 50%), and excellent shear-stress stability during nebulization.²¹⁵ Concurrently, Good Laboratory Practice (GLP)-compliant toxicology studies in rodent and non-rodent species must evaluate both acute and chronic pulmonary toxicity, including bronchoalveolar lavage fluid (BALF) analysis, histopathological examination of lung tissues, and assessment of systemic metal ion biodistribution and clearance.²¹⁶ Phase II (Large Animal Validation) should employ clinically relevant large animal models, such as porcine or non-human primate orthotopic lung cancer models, to validate the pharmacokinetics, local deposition efficiency, and therapeutic efficacy of lead formulations under clinically simulated inhalation conditions.¹⁹⁴ This phase should also establish standardized physical activation parameters tailored to the anatomical constraints of the thorax. Phase III (First-in-Human Phase I Inhalable Clinical Trials) should adopt a dose-escalation design with primary endpoints of safety and tolerability, and secondary endpoints of local tumor response and immune biomarker modulation.¹⁹⁰ Importantly, patient stratification in these early trials should be guided by molecular and TME characteristics, prioritizing populations most likely to benefit: EGFR-TKI-resistant NSCLC, KEAP1/NRF2-mutant tumors, and “cold tumors” with low baseline PD-L1 expression.²¹⁷ This phased roadmap, if systematically executed, will provide the regulatory-grade data necessary to advance lung cancer NDT from bench to bedside while mitigating the translational risks that have historically plagued nanomedicine development.

Despite various challenges, the clinical translation of NDT for lung cancer has a definite direction. It features clear stratification based on clinical scenarios and patient populations. In terms of clinical scenarios, locally recurrent lesions, residual microscopic lesions after surgery, unresectable but localized advanced lesions, and second-line sensitization combined with immunotherapy constitute the most likely “transformation window” to be first breached. The common characteristics of these scenarios include relatively limited lesion burden, susceptibility to local ROS bursts, and clear unmet needs in existing treatment modalities. For the beneficiary population, stratified screening based on molecular subtyping and TME features will be key. Patients with low PD-L1 expression in “cold tumors” may achieve an immune “hot start” through NDT-induced ICD. EGFR-TKI-resistant populations are more susceptible to ROS overload strategies due to compensatory activation of the oxidative stress defense pathway. Redox-dependent tumors (eg, those with KEAP1/NRF2 mutations) and subgroups with abnormal copper/iron metabolism (eg, high SLC31A1 expression and low ferritin expression) may gain selective killing advantages from cuproptosis/ferroptosis coupling strategies. In the future, the development of lung cancer NDT will follow three major trends. First, inhalation NDT will move from concept validation to systematic integration of formulation engineering and device coupling. Future research must address the engineering requirements of dry powder inhalers (DPIs), soft mist inhalers (SMIs), and vibrating mesh nebulizers, focusing on core issues such as nanoparticle shear stress stability during atomization, aerodynamic particle size grading, and mucociliary clearance and escape following alveolar deposition.²⁰⁰ Resolving these obstacles will help realize the practical application of inhalable nanodynamic therapy. Regarding cell death mechanisms, research is evolving from simple reactive oxygen species elevation toward the integration of multiple cell death pathways. Recent studies have revealed that the ¹O₂ produced by SDT not only directly damages organelles but also depletes GSH and inhibits GPX4, thereby introducing apoptotic signals into the ferroptosis pathway. The copper based nanoplatform releases Cu ⁺ under ultrasound activation, triggering cuprotosis by directly binding to acylated DLAT protein. Meanwhile, cuprous ions trigger Fenton-like reactions to further boost reactive oxygen species levels. This creates a mutually reinforcing cell death network that integrates sonodynamic therapy, cuproptosis and chemodynamic therapy.²¹⁸ Recently, a carbon-dot-sensitized Cu₃P sonoenzymatic system, through heterojunction construction, achieved amplified ROS production integrated with cuproptosis-enhanced cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, resulting in primary tumor elimination and distant tumor growth inhibition in lung cancer models.²¹⁹ Another study developed a tumor-microenvironment-responsive self-oxygenating nanoplatform (CaO₂-MD) that synergistically enhanced cuproptosis and sonodynamic therapy, achieving an 80% tumor inhibition rate when combined with PD-L1 blockade.²²⁰ Design strategies focused on crosstalk between cell death pathways will take the place of earlier methods that only aimed to boost reactive oxygen species production. Furthermore, the pairing of nanodynamic therapy and immunotherapy is moving beyond the simple use of PD-1 antibodies toward systematic reconstruction of the immune network. Inhaled STING agonist nanocapsules have been shown to activate the cGAS-STING pathway, promote CAR-T cell infiltration, and induce abscopal effects in lung cancer lesions.²⁰² IL-12 mRNA exosomes, following inhalation, reshape the local pulmonary immune microenvironment and stimulate systemic anti-tumor immunity.¹⁹⁰ The integration of TAM reprogramming and T cell exhaustion reversal strategies will provide an immune amplification circuit for NDT-induced local oxidation. Moreover, a nanomedicine approach that modulates the pre-metastatic niche and inhibits metastatic lung adenocarcinoma (PSMP) via dual mechanisms of PD-L1 blockade and STING pathway activation offers a new paradigm for the deep integration of inhaled NDT and immunotherapy.²²¹

Conclusion

NDT achieves the integration of precise local tumor killing and systemic immune transformation in lung cancer by amplifying ROS in response to the TME. This review systematically elaborates on the adaptation mechanisms and collaborative strategies of four NDT modalities—SDT, CDT, PDT, and RDT—in lung cancer from three perspectives: TME-endogenous activation, multimodal PCD pathway reprogramming, and immune “cold-to-hot” transformation. SDT, owing to its deep penetration advantage, has become the modality best suited to the anatomical characteristics of lung cancer. CDT utilizes acidic pH and H₂O₂) accumulation to achieve endogenous catalysis, while RDT is naturally embedded within the intensive treatment framework of lung cancer radiotherapy. The coupling of death networks effectively circumvents the resistance dilemma induced by single-pathway apoptosis while releasing tumor antigens through ICD, thereby creating favorable response conditions for immune checkpoint inhibitors (ICIs). Inhalable nanoplatforms turn the anatomical characteristics of the lung into favorable pharmacokinetic properties. Examples include size-transformable nanoparticles and nanocapsules carrying STING agonists, which prove capable of achieving lung retention, intelligent response and controllable activation. At the clinical translation level, the main challenges include the lack of orthotopic models, imbalanced evidence across modalities, over-engineering of nanoplatforms, absent safety data for metal ion accumulation in the lungs, and inconsistent physical activation parameters. In the future, locally recurrent lesions, postoperative residual disease, unresectable focal lesions, and immune-combined second-line sensitization are the scenarios most likely to be first addressed by NDT strategies. Patient stratification based on molecular subtyping and TME characteristics will be key to unlocking the clinical value of NDT. These characteristics include low PD-L1 expression in “cold tumors”, EGFR TKI resistant populations, KEAP1/NRF2 mutations, and subgroups with abnormal copper and iron metabolism. Lung cancer nanodynamic therapy is evolving in multiple dimensions: from merely boosting reactive oxygen species to linking diverse cell death pathways, from the supplementary use of PD 1 antibodies to rebuilding the immune network, and from preliminary concept verification to integrated formulation design and device combination. It is poised to become a core driver that reshapes lung cancer treatment strategies from local intervention to systemic management.

Funding Statement

This study was funded by General Program of the Sichuan Provincial Science and Technology–Education Joint Fund Project (2025NSFSC2150) and 2025 Sichuan Provincial Clinical Key Specialty Construction Project (YS000177).

Data Sharing Statement

No new data has been generated, all references are cited in the manuscript.

Ethics Approval and Consent to Participate

Ethics statement is not applicable.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that there are no competing interests associated with the manuscript.