Lysosome-targeted nanomaterials for advanced cancer therapy: Overcoming resistance, activating immunity and amplifying therapeutic synergy

Abstract

Lysosomes were once regarded merely as the cellular “waste disposal” system, but are now widely recognized as pivotal hubs for regulating intracellular homeostasis and have emerged as promising therapeutic targets in cancer treatment. This review systematically explores the interplay between nanomaterials and lysosomal function, focusing particularly on how to leverage this interaction to enhance antitumor efficacy. First, we outline the mechanisms by which nanomaterials modulate lysosomal activity. Next, we review the main antitumor pathways used by lysosome-targeted nanomaterials, such as inhibiting autophagic flux, activating programmed cell death pathways (including cuproptosis, ferroptosis, apoptosis, and pyroptosis), and remodeling the immunosuppressive tumor microenvironment. We also analyze various strategies for synergistic enhancement, such as metabolic intervention and stimuli-responsive combination therapies (such as light-, ultrasound- or ROS-activated), as well as lysosome-targeted approaches for improving conventional chemotherapy and radiotherapy. In conclusion, this review provides a comprehensive overview of current lysosome-targeted nanomedicine research and outlines future directions for translating these strategies into clinical applications.

Graphical abstract

Nanomaterials emerge as a potent antitumor strategy by precisely targeting lysosomes to disrupt cellular homeostasis and activate diverse cell death pathways.

1. Introduction

As dynamic organelles, lysosomes play a crucial role in maintaining cellular homeostasis by degrading and recycling cellular waste¹. Lysosome biogenesis begins in the rough endoplasmic reticulum (ER), where ribosome-synthesized precursors are modified and translocated during translation. These components are then transported in vesicles to the Golgi apparatus, where mannose-6-phosphate tagging directs their packaging into primary lysosomes at the trans-Golgi network². The acidic lumen (pH 4.5–5.0) activates more than 60 hydrolytic enzymes that are essential for the digestion of macromolecules. This process sustains cellular turnover and provides essential metabolic precursors during periods of nutrient scarcity. The process of lysosomal degradation targets a wide range of substrates, which are primarily delivered through phagocytosis, autophagy and endocytosis³. The resulting products are either exported to the cytosol for reuse, or expelled via exocytosis. Therefore, lysosomal clearance is essential for maintaining cellular homeostasis (Fig. 1).

Figure 1.

Schematic diagram of lysosomal biogenesis and degradation pathways.

As single-membrane-bound organelles, lysosomes require two key classes of protein to function: luminal hydrolases, which degrade biomacromolecules in the acidic lumen⁴; and integral membrane proteins, including protective glycosylated large acidic membrane proteins (LAMPs) and homeostatic transporters/channels. Lysosomes are dynamic organelles that interact with multiple systems and function as essential signaling hubs. In summary, lysosomes are multifunctional organelles that play a key role in substrate degradation and are also involved in other essential cellular processes, such as endocytosis, metabolic regulation, ion homeostasis, plasma membrane repair, nutrient sensing and immune signaling⁵ (Fig. 2). Given the fundamental role of lysosomes in multiple cellular activities, it is unsurprising that abnormal lysosome activity is a characteristic of several human diseases. Dysfunction of the lysosome is strongly associated with an increased risk of various diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, lysosomal storage disorders, atherosclerosis, rheumatoid arthritis and cancer6, 7, 8.

Figure 2.

Schematic diagram of lysosomal composition and function.

Lysosomes possess the inherent capacity to degrade damaged organelles and recycle cellular components, a process essential for cellular homeostasis in normal cells that is hijacked by cancer cells to promote their survival and proliferation. The upregulation of autophagy and lysosomal activity constitutes a fundamental mechanism in cancer progression and metastasis, with accumulating evidence indicating that many solid tumors rely on sustained autophagy for growth9, 10, 11. Cancer cells exhibit distinct compositional profiles of lysosomal enzymes, membrane proteins, and associated factors, as well as disrupted sphingolipid metabolism characterized by overexpression of sphingosine kinase and acid sphingomyelinase¹². These modifications compromise lysosomal membrane integrity and function, resulting in the formation of enlarged yet fragile lysosomes. Coupled with enhanced lysosomal biogenesis in cancer, this enlargement enables the sequestration of chemotherapeutic agents and their subsequent exocytosis, thereby fostering drug resistance. Furthermore, elevated phosphatidyl inositol-3 kinase (PI3K) activity in cancer cells stabilizes lysosomes and modulates their size, subcellular localization, and activity¹³. Inhibition of PI3K signaling redirects cell death pathways from caspase-dependent apoptosis to cathepsin-mediated mechanisms¹⁴. Given the emerging recognition of lysosomes as central regulators of metabolic reprogramming in malignancies and their critical role in fulfilling the bioenergetic and biosynthetic demands of progressing tumors, targeting lysosomal function has emerged as a promising therapeutic approach to circumvent treatment resistance and re-sensitize tumors to therapy. Consequently, identifying optimal clinical scenarios for lysosome-directed nanomaterials represents a major research imperative.

Nanomaterials have revolutionized cancer therapy by offering unprecedented advantages in drug delivery, including improved pharmacokinetics, enhanced permeability and retention effects, and tumor-specific targeting capabilities, enabling tailored interventions. The intersection of nanomedicine and lysosomal biology represents a particularly promising frontier, where nanomaterials can induce diverse forms of cell death by modulating lysosomal pathways¹⁵. Nanomaterials can be engineered to specifically target lysosomes through various mechanisms, including pH-responsive designs that exploit the acidic lysosomal environment¹⁶, receptor-mediated endocytosis pathways that culminate in lysosomal delivery¹⁷, and incorporation of lysosome-targeted moieties that achieve selective aggregation in lysosomes¹⁸. Receptor-mediated approaches, for instance, often involve clathrin-dependent internalization, which directs nanoparticles to lysosomes for effective cargo release¹⁹.

The interactions between nanomaterials and lysosomes are complex and bidirectional. On the one hand, lysosomes can degrade nanomaterials in their harsh luminal environment, which is a critical determinant of their fate. On the other hand, nanomaterials can modulate lysosomal function by either enhancing or disrupting processes such as acidification, enzyme activity, membrane integrity, and autophagic flux²⁰. For instance, lysosomal escape triggered by nanomaterials, facilitated by strategies such as polyethylene glycol (PEG) termination and surface composition design, can preserve targeting moieties while altering cellular metabolism. These interactions can be harnessed to trigger various forms of programmed cell death (PCD), including recently characterized pathways such as ferroptosis, pyroptosis, and cuproptosis^21,22, which are emerging as key mechanisms in cancer therapy²³.

This review first examines the fundamental mechanisms that govern the regulation of lysosomal function and nanomaterial–lysosome interactions, with an emphasis on acidification dynamics, degradation processes, and membrane permeabilization phenomena. Surface modifications that enhance therapeutic efficacy through lysosomal escape strategies are specifically highlighted. Secondly, the analysis will explore the activation of PCD pathways in cancer cells by lysosome-targeted nanomaterials, with a particular focus on emerging pathways such as cuproptosis and their interplay with autophagy and immunogenic responses. Particular focus is placed on novel nanomaterials that disrupt lysosomal integrity to induce immunogenic cell death (ICD). Finally, the analysis will explore the activation of PCD pathways in cancer cells by lysosome-targeted nanomaterials, with a particular focus on emerging strategies to overcome chemoresistance in lysosome-targeted therapies.

Throughout this review, cutting-edge examples from recent literature are highlighted (Table 1^18,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69). By systematically analyzing design principles, mechanistic underpinnings, and therapeutic outcomes of lysosome-targeted nanomaterials, this review aims to provide insights guiding the development of more effective and selective cancer nanotherapeutics. The convergence of advanced nanomaterial engineering with a deepening understanding of lysosomal biology holds promise for yielding innovative strategies that exploit cancer-specific vulnerabilities while minimizing effects on normal tissues.

Table 1.

Representative lysosome-targeted nanomaterials and their mechanisms in cancer therapy.

Functional group	Nanomaterial	Lysosome-targeted therapeutic strategy	Nanomaterial-mediated lysosomal modulation	Tumor cell	Ref.
Autophagy-targeting systems	mTEVs	Phagocytosis	Lysosomal degradation of NPs	4T1	24
	6EPP@si	Phagocytosis	Self-lysosome escape	4T1	25
	TeDNBs-HO	Autophagy dysfunction	Lysosomal damage	4T1	26
	PBC NPs	Autophagy dysfunction, PDT	Lysosomal dysfunction	OSC-3	27
	Lip@Pt3/Lip-cRGD@Pt3 NPs	Autophagy dysfunction, apoptosis	Lysosomal damage	A549	28
	LDH NPs	Autophagy dysfunction, apoptosis	Lysosomal damage	B16F10, CT26	29
	BTO/BP-HA	Autophagy inhibition, apoptosis,	Lysosomal degradation of black phosphorus	HeLa	30
	PP/siRNA/HA	Autophagy inhibition	Lysosomal alkalinization	A549, A549/T	31
PCD inducers	PSNAs	Pyroptosis, necroptosis	Lysosomal damage	SKOV-3, B16-OVA	32
	TAENmi	Pyroptosis	Lysosome-mitochondria cascade damage	4T1, MCF-7, CT-26	33
	CuGA	Cuproptosis, pyroptosis	Lysosomal-mitochondrial cascade damage	4T1	34
	VS2-PEG	Ferroptosis, ICI	Lysosomal escape	CT26	35
	ZnO@BBCs	Ferroptosis	Lysosomal escape	A549/DDP	36
	PC(coBP)Ca_(Er+1M + Yov + Nko)	Ferroptosis, phagocytosis	Lysosomal escape	CD24high	37
	M-CaCO3@L-PEG NPs	Paraptosis, apoptosis	Lysosomal degradation of NPs	4T1	38
	DNAzyme biocapsule	Apoptosis	Lysosomal escape	MCF-7	39
	JAuNR-Pt	Apoptosis	Lysosomal escape	MCF-7	40
	Nab-PTX	Apoptosis	Lysosomal degradation of protein	HCT116	41
	(Nig + DAC)@HmA	Pyroptosis	Lysosomal escape	MB49	42
Immunomodulatory systems	LTANPs	ICI	Lysosomal damage	B16F10	18
	ICB-LPs	ICI	Lysosomal degradation of PD-L1	CT26, 4T1	43
	DCNV(CSD)	Immunotherapy	Lysosomal escape	GL261	44
	AlNEs- OVA-CpG	Immunotherapy	Lysosomal escape	EG7-OVA	45
	Si9GM	ICI	Lysosomal escape	B16-OVA	46
	M-CS-SA	Immunotherapy	Lysosomal escape	4T1	47
	NLTC-BMS/CAT-PDA	Immunotherapy	Lysosomal degradation of protein	B16F10	48
	MILND	Immunotherapy	Lysosomal degradation of PD-L1	4T1	49
	Nano-IFNγ/Zole	Immunotherapy	Reduced lysosomal acidification	CT-26	50
Metabolic interference agents	ZnO2@PDA-Fe (Z@P-F)	CDT, PTT	Lysosomal escape	4T1	51
	AbCholB	Glucose deprivation therapy	Lysosomal damage	MDA-MB-231	52
	GOx-LYTAC	Starvation therapy	Lysosomal degradation of cell membrane and protein	HepG2	53
Stimuli-responsive platforms	Tf-Te/HCQ	PTT, PDT	Lysosomal alkalinization	4T1	54
	839/CG	Apoptosis, PTT	Lysosomal damage	4T1	55
	CaO2@PCN	SDT, interference therapy	Lysosomal degradation of NPs	4T1	56
	C1 nanofibrils/nanorods	Light irradiation	Lysosomal damage	MuM-2B	57
	OCPNs	PTT	Lysosomal escape	A549	58
	Fe3O4@BSA-TAFeIII	PTT, ferroptosis, apoptosis	Lysosomal degradation of NPs	4T1	59
	DM NPs	PTT, PDT, apoptosis	Lysosomal damage	CT-26 Mito-FAP	60
	CPPD1	PDT, ICD	Lysosomal degradation of PD-L1	CT26	61
	TAN	PDT	Lysosomal escape	B16–F10	62
Chemo-/radiotherapeutic platforms	LTSPN	Chemotherapy	Lysosomal damage	EJ	63
	PC-PLL-β1	Chemotherapy, immunotherapy	Lysosomal degradation of protein	Panc-1, Panc02	64
	IR780@LDs-Fe3O4/OA	Chemotherapy, SDT	Lysosomal dysfunction	MCF-7/ADR	65
	PC-DOX-T	Chemotherapy	Lysosomal degradation of NPs	MCF-7/ADR	66
	siHyal1taLRNSDOX	Chemotherapy	Lysosomal escape	4T1	67
	Au@Cu2-xSe NPs	Radiotherapy, apoptosis	Lysosomal alkalinization	U-87MG	68
	CeVO4	Radiation therapy	Lysosomal escape	LN229, A172	69

2. Lysosomal function regulation and nanomaterial interactions

Having established the pivotal role of lysosomes in cancer biology and the general principles of lysosome-targeted therapy in the introduction, we now delve into the specific mechanisms at play. This section provides a detailed examination of the key aspects of lysosomal dysregulation in cancer and the multifaceted interactions between nanomaterials and this organelle. A deep understanding of these fundamental processes is crucial for the rational design of effective lysosome-targeted nanomedicines^70,71. Understanding and manipulating fundamental lysosomal processes is key to the success of lysosome-targeted cancer therapy. Dysregulation of acidification, degradation capacity, or membrane integrity can trigger catastrophic cellular failure⁷². Cancer cells depend more heavily on lysosomal functions for nutrient scavenging and stress adaptation, creating vulnerabilities that can be exploited in nutrient environments where lysosomal catabolic capacity is mobilized in response to changes⁷³. Nanomaterials interact bidirectionally with lysosomes: while lysosomal acidity may degrade nanocarriers, engineered nanoparticles can actively disrupt pH homeostasis, permeabilize membranes, or impair enzyme activity (Fig. 3). Strategic modulation of these interactions enables the selective killing of tumor cells while sparing healthy tissues. This section dissects key regulatory mechanisms and nanomaterial–lysosome interactions, providing a foundation for the rational design of nanomedicines.

Figure 3.

Interaction between nanomaterials and lysosomes and related strategies.

2.1. Lysosomal dysregulation

The efficacy of lysosome-targeted therapy hinges on the unique dysregulated state of lysosomes in cancer cells. Unlike the tightly regulated lysosomes found in normal cells, those in cancer cells exhibit distinct biochemical and physical aberrations that could be exploited for therapeutic purposes. This subsection explores these characteristic dysregulations, which form the basis for selective targeting by nanomaterials. Maintaining lysosomal homeostasis, characterized by tightly regulated acidification, enzymatic activity, and fusion dynamics, is essential for cellular viability⁷¹. However, cancer cells exploit these processes to promote proliferation and survival under metabolic stress. Lysosomal dysregulation represents a hallmark of many cancer types, manifesting through altered pH gradients, aberrant enzyme expression, and compromised membrane integrity⁷⁴. These cancer-specific phenotypes create unique vulnerabilities that can be selectively targeted by engineered nanomaterials. Notably, cancer cells often exhibit increased lysosomal size, number, and peripheral distribution compared to normal cells, alongside upregulated cathepsin activity and altered membrane composition⁷⁵. Such dysregulation not only supports cancer progression by facilitating invasion and metastasis but also contributes to therapy resistance by sequestering and neutralizing conventional chemotherapeutics⁷⁶. Identifying distinct lysosomal dysregulation signatures across different cancer types enables the development of precision targeting strategies that exploit these aberrations while sparing normal tissues.

2.1.1. Lysosomal pH instability

The precise regulation of lysosomal pH is fundamental to its hydrolytic function, and its dysregulation represents a primary target for nanomaterial intervention. Lysosomal pH instability, a common feature in cancer cells, provides a key biochemical handle for designing tumor-selective therapies. The acidic lysosomal environment provides a universal trigger for smart nanocarriers, where pH-responsive materials undergo charge reversal or structural transitions to enable tumor-selective drug release⁷⁷. For example, hyaluronic acid-based nanogels (HA@Dox) exhibit pH-responsive release in lysosomes, while DNA nanostructures consume protons to reduce lysosomal acidity and attenuate hydrolase activity, thereby improving intralysosomal retention⁷⁸. Beyond drug delivery, nanoparticles can actively modulate pathological lysosomal pH through normalization to restore enzyme function or alkalinization to block autophagy, as observed in systems that generate alkalinization and disrupt cathepsin activity⁷⁹. This bidirectional control exemplifies how nanomaterials convert a fundamental biological feature into a therapeutic control point for applications such as tumor-selective therapy⁸⁰.

Zhang et al.⁵⁴ developed a tumor-activated nano-drug delivery system (Tf-Te/HCQ) for the synergistic treatment of breast cancer. This system utilized transferrin (Tf) as both a biomimetic mineralization template for tellurium nanoparticles (Te NPs), as well as a carrier for the autophagy inhibitor hydroxychloroquine (HCQ). Disulfide bond reconstruction enabled the nanoparticles to self-assemble and conferred glutathione (GSH)-responsive drug release within tumor cells. Under near-infrared (NIR) laser irradiation, Tf-Te/HCQ generated localized hyperthermia and reactive oxygen species (ROS) for phototherapy. At the same time, the high intratumoral GSH concentration triggered nanoparticle disintegration, releasing HCQ and Fe²⁺. They then triggered lysosomal alkalinization and elevated osmotic pressure, synergistically leading to lysosomal destruction. Consequently, autophagy was inhibited during the digestive stage of autophagic flux. The tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6% in 4T1 tumor-bearing mice, demonstrating enhanced therapeutic outcomes. This targeted approach offers a promising strategy for improving the precision and efficacy of tumor phototherapy by regulating lysosomal alkalinization.

Furthermore, Xu et al.⁶⁸ reported that core-shell copper selenide-coated gold nanoparticles (Au@Cu_2-xSe NPs) significantly enhanced the radiotherapy efficacy against orthotopic glioblastoma by concurrently inhibiting protective autophagy flux and DNA repair in tumor cells. The nanoparticles effectively alkalized lysosomal pH via hydroxyl ions generated from a Fenton-like reaction with H₂O₂, thereby blocking autophagic degradation and increasing SQSTM1/p62 protein accumulation without altering its mRNA levels. Furthermore, Au@Cu_2-xSe NPs promoted ubiquitin-mediated proteasomal degradation of the critical DNA repair protein Rad51, specifically impairing the homologous recombination pathway. The median survival time increased to 42 days for the mice in the experimental group, compared to 26 days for the untreated mice in the control group. These results suggest that Au@Cu_2-xSe NPs perform excellently in inhibiting the growth of tumor by influencing the lysosomal pH of tumor cells and preventing damaged DNA repair. This strategy shows great potential for the treatment of other radioresistant tumors.

2.1.2. Functional impairment

Beyond acute physical damage, subtler forms of lysosomal functional impairment can be equally lethal to cancer cells. This strategy focuses on disrupting the organelle's biochemical activity without immediate membrane rupture, leading to a more progressive yet ultimately fatal cellular stress response. Subtle lysosomal dysfunction, which is characterized by enzyme inactivation and ion gradient collapse, can initiate irreversible stress responses by impairing acidification and hydrolase activity. Nanoparticles that alkalinize lysosomes, sequester cofactors, or generate intraluminal precipitates induce lysosomal incapacitation without immediate membrane rupture⁸¹. This stealthier approach allows progressive accumulation of lipofuscin-like aggregates and proteotoxic stress, ultimately triggering paraptosis or apoptosis and providing time-dependent therapeutic effects advantageous for sustained tumor suppression.

Ma et al.²⁷ developed a lysosome-targeted small-molecule conjugate (PBC, pheophorbide A-bisaminoquinoline) that self-assembles into nanoparticles at physiological pH and undergoes pH-triggered transformation into nanofibrils (NFs) within tumor cell lysosomes. This morphological transition induced lysosomal dysfunction, impaired autophagy (evidenced by increased LC3B-II and p62 levels), and triggered cytoplasmic vacuolation, conferring significant antitumor activity against oral cancer when used as a monotherapy. Importantly, PBC-mediated photodynamic therapy (PDT) generated enhanced lysosome-specific ROS and overcame autophagy-induced treatment resistance by blocking autophagic flux. This dual mechanism achieved complete tumor ablation in oral cancer xenografts within minimal treatment cycles, leveraging prolonged intratumoral retention of PBC NFs for repeated laser-triggered activations per administered dose. The system demonstrated favorable biosafety in murine models, with no significant weight loss or organ toxicity observed.

Additionally, Shi et al.⁶⁵ engineered endogenous lipid droplets (IR780@LDs-Fe₃O₄/OA) to enable cascade-targeted sonodynamic therapy (SDT) for the reversal of multidrug resistance (MDR) in breast cancer. IR780@LDs-Fe₃O₄/OA was efficiently enriched in tumor sites in a static magnetic field to guide tumor treatment under visualization. IR780@LDs-Fe₃O₄/OA-mediated lysosome-targeted SDT strategy triggered an increase in lysosomal membrane permeability to alleviate the lysosomal sequestration of doxorubicin (DOX), and inhibited P-glycoprotein activity to reduce DOX efflux, thus synergistically enhancing DOX access to the nucleus and overcoming MDR. This cascade-targeted SDT significantly increased the sensitivity of MDR cells to DOX, increasing the IC₅₀ value of DOX by approximately 10-fold. Moreover, the strategy was additionally confirmed to effectively inhibit MDR-associated gene expression and reshape the transcriptomic profiles of MDR tumor cells. This study establishes lysosome-targeted SDT as a promising strategy for reversing MDR in breast cancer when combined with chemotherapy.

2.1.3. Lysosomal damage

In contrast to functional impairment, direct and irreversible lysosomal membrane permeabilization (LMP) represents a more acute and catastrophic intervention. Inducing LMP triggers the rapid release of potent hydrolases into the cytosol, effectively flipping the lysosome's homeostatic function into a potent cell death signal82, 83, 84. Irreversible lysosomal damage culminates in catastrophic organelle failure, marked by the lethal release of hydrolytic enzymes into the cytosol that drives cell death⁸⁵. Engineered nanoparticles induce this damage through osmotic swelling or direct membrane rupture, activating apoptosis, necrosis, or inflammatory pathways via liberated hydrolases^86,87. Cancer cells with characteristically enlarged lysosomal compartments and diminished membrane stability exhibit heightened susceptibility to such damage. Nanomaterials exploiting this vulnerability achieve spatiotemporally controlled organelle destruction through intralysosomal aggregation, in situ gas generation, or photothermal-triggered bursting.

Xing et al.¹⁸ demonstrated a lysosomal-targeting aggregated nanoparticle (LTANP) that can selectively induce LMP in cancer cells. Through rational surface engineering, LTANP maintained stability in circulation but detached a PEG shell in the acidic tumor microenvironment (TME). This exposed a protein nanocapsule core functionalized with mannose-6-phosphate ligands and protonatable 1-vinyl imidazole. This enabled cation-independent mannose-6-phosphate receptor (CI-M6PR)-mediated cellular uptake and lysosomal trafficking. In acidic lysosomes (pH 4.5–5.0), 1-vinyl imidazole protonation reduced electrostatic repulsion, triggering nanoparticle aggregation. The resulting aggregates inhibited exocytosis, causing irreversible lysosomal swelling, LMP and impaired autophagy (Fig. 4¹⁸). Consequently, this aggregation-induced LMP elicited robust ICD, characterized by calreticulin exposure, HMGB-1/ATP release, dendritic cells (DCs) maturation, and enhanced CD8⁺ T cells infiltration. The treatment reversed immunosuppression by reducing MDSCs/Tregs and polarizing M2 to M1 macrophages, converting “immune-cold” tumors to “hot”. Furthermore, LTANP synergized with PD-L1 blockade to amplify T cell immunity, suppress metastasis and establish long-term immune memory in melanoma models. This work demonstrates that rationally engineered LTANP can selectively induce LMP of tumor cells and evoke robust ICD-associated antitumor immunity, providing novel insights for the development of advanced nanoparticle-based cancer treatment.

Figure 4.

(A) Schematic illustration of PEG shell detachment in the acidic TME (pH 6.5) and protein nanocapsule aggregation in the lysosomal microenvironment (pH 4.5). (B) A schematic illustration of the biomimetic strategy for lysosome-targeted LTANP aggregation to induce LMP and ICD for cancer immunotherapy. (C) Bio-TEM images of B16F10 cells treated with different formulations (scale bar: 2 μm). Orange rectangles: Regions of interest (scale bar: 0.5 μm); purple arrows: autophagosomes; red arrows: lysosomes. (D) Acridine orange staining of B16F10 cells after 6 h treatment with different formulations (scale bar: 10 μm). (E) Representative images of galectin-3 staining after 6 h treatment with different formulations (scale bar: 10 μm). (Adapted with permission from Ref. 18).

Other studies have also explored lysosome-targeted agents as a means to induce cancer cell death. He et al.³² engineered peptide-driven proton sponge nano-assemblies (PSNAs), which induce lysosomal rupture after endocytosis, triggering concurrent pyroptosis/necroptosis and ICD to remodel TME. Similarly, Hou et al.⁶³ developed a lysosome-targeted self-condensation prodrug-nanoplatform (LTSPN) that disrupts lysosomal membrane integrity via acidic microenvironment-triggered reactions, effectively overcoming lysosomal drug sequestration and suppressing resistant tumors. In a complementary approach, Wang et al.²⁶ designed omeprazole-loaded tellurium nanobullets (TeDNBs-HO) that impair lysosomal function by alkalizing pH and downregulating LAMP1, thereby blocking autophagic flux and synergizing with autophagy induction for enhanced therapy. Collectively, these studies demonstrate that targeted lysosomal damage is a powerful mechanism to amplify cell death and overcome drug resistance in cancer treatment.

2.1.4. Lysosome-mitochondria cascade damage

The strategic disruption of lysosomes often initiates a destructive domino effect on other organelles, particularly mitochondria. This cascade amplification leverages the intrinsic crosstalk between organelles to enhance therapeutic efficacy and overcome monotherapeutic resistance. Lysosomal damage often propagates to mitochondria via calcium flux, ROS spread, or protease-mediated Bid cleavage, amplifying cellular stress and mitochondrial dysfunction. Nanoparticles engineered for sequential organelle targeting maximize this cascade effect by initially disrupting lysosomes to release proteases, which activate mitochondrial effectors, followed by secondary mitochondrial targeting to compound energy collapse⁸⁸. This domino strategy enhances cell death signals and overcomes compensatory mechanisms. Materials coordinating spatiotemporal damage across organelles represent a frontier in organelle-targeted therapy.

The efficacy of mitochondrial-targeted nanoparticles is often limited by their macromolecular nature, which impedes endosome/lysosomal escape. To overcome this limitation, Liu et al.³³ developed a trimodular acid/enzyme-gated nanoplatform (TAEN^mi) for lysosome-to-mitochondria cascade delivery in cancer immunotherapy. In an acidic endosomal environment, TAEN^mi disassembles and is subsequently cleaved by lysosomal cathepsin B. This process enables the released cargo to be efficiently transported to the mitochondria. The resulting mitochondrial stress activates the intrinsic apoptotic pathway and the caspase-3/GSDME cascade, enhancing cancer cell killing efficacy by nearly two orders of magnitude compared to lysosomal stress. Furthermore, TAEN^mi potently stimulates both innate and adaptive immunity, inducing a robust antitumor immune response in multiple mouse models. This work provides a strategic nanoplatform for precise targeting of subcellular organelles and a powerful toolbox for probing location-dependent signaling.

2.2. Nanomaterial–lysosome interactions

Beyond the intrinsic dysregulation of cancer lysosomes, the physicochemical properties of nanomaterials themselves critically determine their fate and function within the cell. This subsection shifts focus to the dynamic interplay at the nano–bio interface, exploring how engineered nanomaterials are processed by lysosomes and, in turn, how they can be designed to modulate or escape this compartment. The interface between engineered nanomaterials and lysosomes represents a dynamic interaction zone where physicochemical properties determine therapeutic outcomes. These interactions are governed by multiple factors including nanomaterial composition, size, surface charge, and functionalization, which collectively influence cellular uptake, lysosomal trafficking, and subsequent biological responses²⁰. Strategic manipulation of these parameters can direct nanomaterials toward specific lysosomal compartments, trigger controlled LMP, or modulate enzymatic activity. The unique microenvironment within lysosomes-characterized by acidic pH, high enzymatic activity, and redox potential-provides distinctive triggers for stimuli-responsive nanomaterials designed to release therapeutic payloads or induce structural transformations selectively within cancer cells⁸⁹. The following subsections explore key interaction modalities between nanomaterials and lysosomes.

2.2.1. Lysosomal sequestration and degradation

The inherent degradative function of the lysosome, while a barrier to some therapeutics, can be co-opted as a strategic gateway for nanomaterial-based interventions. By designing nanomaterials to be selectively processed within lysosomes, researchers can harness this compartment for targeted drug release, protein degradation, and immune activation. As a key lysosomal function, degradation relies on the coordinated action of >60 hydrolases, with cancer cells often overexpressing proteases like cathepsins to facilitate invasion by degrading the extracellular matrix and contributing to tumor growth⁹⁰. Critically, this degradative machinery is strategically repurposed for therapy: nanocarriers engineered for lysosomal trafficking deliver enzyme inhibitors or protease-activated prodrugs, converting lysosomes into activation chambers for targeted payload release⁹¹. Such selective intervention simultaneously disrupts the tumor's degradation capacity while enabling therapeutic precision. Furthermore, nanoparticles designed for high-uptake and lysosomal accumulation drive degradation of oncogenic proteins or enhance antigen processing. Endocytosed nanomaterials sequestered in lysosomes can prolong antigen preservation, augmenting cross-presentation for antitumor immunity.

Lee et al.⁴³ developed photo-crosslinked liposomes incorporating an anti-PD-L1 peptide (ICB-LPs), which enhances PD-L1 multivalent binding. ICB-LPs exhibited high serum stability and a uniform size. In vitro, ICB-LPs efficiently promote multivalent binding to PD-L1 on tumor cells, inducing its endocytosis and subsequent delivery to lysosomes. This process results in sustained PD-L1 degradation for up to 72 h, in sharp contrast to anti-PD-L1 mAbs, which only promote rapid PD-L1 recycling within 9 h. ICB-LPs effectively enhanced a potent T cell-mediated antitumor immune response by blocking the PD-L1/PD-1 axis. In vivo, ICB-LPs accumulated efficiently in tumors via passive and active mechanisms. Administration in colon tumor-bearing mice resulted in significant tumor growth suppression and prolonged survival, attributed to durable lysosomal PD-L1 degradation, increased cytotoxic T lymphocyte infiltration, granzyme B secretion, and reduced regulatory T cells. Collectively, this study demonstrated that ICB-LPs promote the multivalent binding of PD-L1 for trafficking towards the lysosomes instead of the recycling endosomes.

Lysosome-targeted chimera-mediated protein degradation appeared as a promising tool for extracellular signal interference but was limited by several lysosome-trafficking receptors and inadequate in vivo degradation efficiency. Here, Liu et al.⁶⁴ developed a tumor-targeted multivalent aptamer assembly (PC-PLL-β1), which is designed to selectively degrade extracellular transforming growth factor-beta (TGF-β) for lysosome degradation with high tumor specificity. This nanoplatform facilitated cell recognition-internalization and lysosomal delivery in pancreatic cancer cells and pancreatic stellate cells. In vivo, the assembly exhibited superior tumor-specific accumulation and prolonged intratumor retention. This resulted in potent TGF-β signaling blockade, stromal remodeling (reduced α-SMA, collagen deposition), and reversal of immunosuppressive cell polarization (decreased Tregs, M2-TAMs, MDSCs), thus enhancing the therapeutic effects of gemcitabine and ovalbumin (OVA). Consequently, PC-PLL-β1 significantly enhanced the therapeutic efficacy of chemotherapy and immunotherapy by reprogramming the tumor stroma and immunosuppressive niche. This study will provide an alternative strategy for extracellular protein intervention and adjuvant therapy in the treatment of pancreatic cancer.

Tumour-derived extracellular vesicles (TEVs) contain abundant tumor antigen molecules. However, anti-phagocytosis signals on their surface enable these vesicles to evade the immune system. To overcome these problems, Ding et al.²⁴ developed a universal nano-masking strategy involving iron oxide hydroxide nanocomposites to non-discriminatively cloak immuno-evasive ligands (such as CD47) on TEVs. This ex vivo process creates masked TEVs (mTEVs) that retain tumor antigens while evading phagocytosis inhibition. Upon reintroduction, mTEVs exhibited significantly enhanced uptake by DCs and macrophages, facilitated by the physical masking of “don't eat me” signals and exposure of “eat me” signals. Following internalization, the lysosomal-responsive nanocomposite degraded, releasing TEV cargo and generating ROS, which synergistically promoted DCs maturation via STING pathway activation and macrophage repolarization towards an M1 phenotype. In vivo, mTEVs demonstrated potent tumor-specific accumulation, inhibited primary tumor growth and lung metastasis in 4T1 models, and reshaped TME by increasing CD8⁺ T cell infiltration and M1/M2 macrophage ratios. Crucially, this approach proved feasible in clinical malignant pleural effusion samples, where autologous mTEVs enhanced DCs maturation, macrophage repolarization, and tumor antigen-specific T cell responses without the systemic toxicity associated with anti-CD47 antibodies. This masking strategy eliminates the anti-phagocytosis block commonly found in clinical samples and can be universally applied to all patient-specific TEVs as tumor antigenic agents to enhance immunotherapy.

2.2.2. Lysosomal escape mechanisms

Conversely, for therapeutic cargoes that require cytosolic or nuclear delivery, such as nucleic acids and certain proteins, bypassing lysosomal degradation is paramount. Advanced nanomaterials are engineered with “escape” functionalities that allow them to breach the lysosomal membrane, thereby ensuring their bioactive payloads reach intracellular targets intact. Bypassing lysosomal degradation is critical for cytosolic/nuclear delivery of nucleic acids or protease-sensitive drugs. Escape-capable nanomaterials employ proton-sponge polymers, membrane-fusogenic peptides, or stimuli-triggered responses to breach lysosomal membranes, such as modifications like phenylboronic acid that improve tumor therapeutic efficacy by enhancing lysosome escape⁹². The “squeezing-out” mechanism, where PEG-terminated nanomaterials preserve targeting moieties during escape, is supported as a process for lysosomal disruption²⁰. Advanced systems, such as pH-responsive nanocarriers, respond to acidic lysosomal environments to achieve endo/lysosomal escape and cytosolic delivery, enabling efficient gene editing and chemotherapeutic activation^93,94. These technologies protect therapeutic cargos while enabling access to subcellular targets, significantly enhancing druggability for applications like gene editing and immune activation⁹⁵.

Ding et al.²⁵ developed a dual stimuli-responsive nanoimmunomodulator (6EPP@si) that co-delivers an ER-targeted photosensitizer (6E) and siCD47 to synergistically activate macrophage and T cell antitumor immunity. The nanoparticle responds to acidic pH and high GSH in TME, facilitating lysosomal escape via the proton sponge effect and subsequent nanocleavage for precise payload release. Following lysosomal escape, siCD47 downregulates the “don't eat me” signal while ER-localized 6E generates ROS to induce ICD, promoting calreticulin surface exposure (“eat me” signal). This dual modulation significantly potentiates macrophage phagocytosis of tumor cells while stimulating DCs maturation, leading to subsequent cytotoxic T lymphocyte activation. In tumor models, 6EPP@si demonstrates the potential to eradicate tumor and inhibit metastasis, highlighting its potential for enhancing cancer immunotherapy.

A biomimetic dendritic cell-based nanovaccine was developed by coating copper-selenium nanoparticles (CS NPs) with membranes from matured DCs⁴⁴. The CS NPs serve three critical functions: inducing ICD in tumor cells to expose tumor-associated antigens (TAAs), facilitating lysosomal escape of tumor-associated antigens to enhance MHC-I presentation, and releasing copper ions to promote T cell proliferation. The lysosomal escape of TAAs is mediated by versatile CS NPs, which operate through dual mechanisms: generating ROS to cause lysosomal damage and producing OH⁻ to induce lysosomal charge conversion, both of which facilitate TAA release. In aggressive glioblastoma and metastatic melanoma models, CS NPs elicited robust CD8⁺ T cell responses, suppressed primary and metastatic tumor growth, and generated splenic memory T cells that prevented tumor recurrence. This strategy enhances MHC-I antigen presentation by facilitating the lysosomal escape of TAAs, positioning it as a highly promising approach for antitumor immunotherapy in the future.

Chen et al.⁴⁵ developed a hybrid nano-vaccine platform (AINEs) by incorporating aluminum hydroxide into MF59 nanoemulsions that had been modified at the surface. This design leveraged the antigen-adsorbing capacity of aluminum hydroxide and the immunostimulatory properties of MF59. The system efficiently co-loaded OVA antigen and CpG oligonucleotide adjuvant via electrostatic interactions. Following subcutaneous administration, AINEs-OVA-CpG demonstrated enhanced drainage to lymph nodes and preferential uptake by antigen-presenting cells, facilitating cytosolic delivery via lysosomal escape. This promoted robust antigen cross-presentation and DCs maturation, inducing potent antigen-specific CD8⁺ T cell responses alongside balanced Th1/Th2 immunity. In EG7-OVA tumor model, AINEs-OVA-CpG achieved superior tumor suppression compared to MF59 + OVA + CpG or aluminum hydroxide alone, attributed to elevated IFN-γ production and cytotoxic T cell activation. The formulation exhibited favorable safety properties and utilized clinically approved components, highlighting its potential for use in the development of subunit vaccines that require cellular immunity.

3. Antitumor mechanisms of lysosome-targeted nanomaterials

Building upon the foundation of how nanomaterials interact with and modulate lysosomal function, this section transitions to the therapeutic outcomes of these interactions. We systematically categorize and discuss the primary antitumor mechanisms activated by lysosome-targeted nanomaterials, which extend beyond simple organelle disruption to encompass complex cell death signaling and immunomodulation. Lysosomal disruption exploits the altered metabolism of cancer cells to trigger three key outcomes: impaired autophagy, PCD pathways and immunomodulation⁸². Specifically, lysosomal damage impairs autophagic flux, trapping autophagosomes and preventing the degradation of cytotoxic cargo, and this accumulation can be intrinsically lethal or sensitize cells to other death signals⁹⁶. Furthermore, nanomaterials designed to induce cuproptosis, ferroptosis, or pyroptosis target unique metabolic vulnerabilities in tumor cells, such as heightened iron or copper dependence^97,98. Additionally, lysosomal damage releases damage-associated molecular patterns (DAMPs), converting immunologically cold tumors into hot microenvironments that enhance antigen presentation and immune infiltration^99,100. This tripartite capability of disrupting protective autophagy, directly killing tumor cells via multiple mechanisms, and activating the immune system positions lysosome-targeted nanotherapeutic platforms at the forefront of next-generation combination therapies, offering enhanced specificity and utilization efficiency¹⁰¹ (Fig. 5). A systematic understanding of these death mechanisms and immunomodulatory outcomes is enabled by lysosome-targeted nanomedicines.

Figure 5.

Antitumor mechanisms of lysosome-targeted nanomaterials.

3.1. Autophagic flux disruption

Autophagy, a double-edged sword in cancer, can promote cell survival under stress. A key therapeutic strategy, therefore, involves not merely inducing autophagy but critically blocking its final stage, the autophagic flux, which leads to the accumulation of toxic intermediates and metabolic catastrophe. Completion of autophagy requires functional autophagosome-lysosome fusion, a process dysregulated in cancers through impaired SNARE complex assembly or Rab7-HOPS interactions, thereby inhibiting autophagic flux to promote tumor survival^102,103. Nanoparticles disrupt this fusion machinery via lysosomal alkalinization, direct fusion inhibition, or targeting of Rab GTPases/SNARE complexes, trapping cancer cells in futile autophagy. This blockade prevents recycling of metabolic substrates (like amino acids, fatty acids), causing biosynthetic precursor depletion, while inducing accumulation of undegraded substrates, including damaged mitochondria and protein aggregates¹⁰⁴. The resulting mitochondrial ROS leakage and proteotoxic stress exacerbate organelle damage and deplete functional protein reserves. By synergizing with therapies that increase autophagic demand, this strategy intensifies metabolic stress, overcoming cancer cells’ reliance on autophagy for survival. Consequently, nanomaterials that selectively impair fusion dynamics offer a targeted approach to circumvent autophagy-mediated therapy resistance¹⁰⁵.

Liang et al.²⁸ designed a novel Golgi apparatus-targeted platinum(II) complex Pt3, which demonstrated significantly enhanced anticancer efficacy compared to cisplatin. Pt3 selectively accumulated in the Golgi apparatus of lung cancer cells, inducing substantial Golgi stress characterized by fragmentation of the organelles, downregulation of key structural proteins and disruption of transport and glycosylation dependent on the Golgi apparatus. This stress triggered Golgi autophagy but the formation of autolysosomes may have blocked the autophagic flux. Importantly, Pt3 also impaired the fusion of autophagosomes and lysosomes, likely through the downregulation of GRASP55 and cathepsin D, thereby creating a dual blockade in autophagic flux. This dysregulation led to proteostasis collapse and apoptosis. Pt3 displayed profoundly enhanced cytotoxicity relative to cisplatin against lung carcinoma cells in vitro and maintained efficacy in cisplatin-resistant lines. In vivo, intratumoral administration of Pt3 achieved complete tumor eradication in immunocompetent lung carcinoma mouse models, while its nano-encapsulated form administered intravenously also showed potent tumor growth inhibition. This work establishes Golgi stress-mediated dual autophagy flux regulation as a novel and efficient mechanism for platinum-based anticancer therapy.

Extending this paradigm of autophagic flux disruption, a series of nanomaterials has been developed to enhance antitumor efficacy through distinct mechanisms. Zhang et al.²⁹ showed that layered double hydroxide nanoparticles (LDH NPs) neutralize acidic pH in TME and selectively block autophagosome-lysosome fusion in tumor cells, inducing apoptosis and remodeling the tumor immune microenvironment for potent antitumor immunity. Fan et al.³⁰ developed a sonocatalytic heterojunction nanocatalyst (BTO/BP-HA) that generates H₂ under ultrasound to disrupt mitochondrial function, while its degradation elevates lysosomal pH, inhibits autophagic flux, and synergistically promotes immune activation. Similarly, Wang et al.³¹ designed CD44-targeted nanoassemblies (PP/siRNA/HA) that co-deliver paclitaxel and Mdr1 siRNA, where the polyethylenimine component blocks autophagic flux by lysosomal alkalization, overcoming MDR via concurrent inhibition of efflux pumps and pro-survival autophagy. Together, these examples establish autophagic flux disruption as a powerful platform mechanism for nanomaterials, offering a means to synergize with and enhance the efficacy of diverse treatment modalities.

3.2. Activation of PCD pathways

Beyond disrupting the pro-survival function of autophagy, lysosome-targeted nanomaterials are potent inducers of various PCD pathways. The strategic disruption of the lysosome acts as a trigger point for multiple lethal signaling cascades, enabling a multi-pronged attack on cancer cells that can circumvent resistance to single death pathways. Lysosome-targeted nanomaterials demonstrate remarkable versatility in inducing diverse non-apoptotic cell death mechanisms, expanding the therapeutic arsenal against resistant cancers. This capability to integrate multiple death pathways, including necroptosis, pyroptosis, ferroptosis, and metabolic disruption like cuproptosis, addresses a key challenge in oncology: acquired resistance to single-pathway targeted therapies¹⁰⁶. By disrupting lysosomal integrity, these nanomaterials initiate DAMP-mediated signaling cascades, effectively overcoming compensatory survival adaptations. Strategically exploiting lysosomes as signaling hubs enables circumvention of resistance to conventional single-pathway therapies.

3.2.1. Cuproptosis induction

The recent discovery of cuproptosis has opened new avenues for cancer therapy. Lysosome-targeted nanomaterials provide an ideal platform to confine copper release to malignant cells, thereby maximizing cuproptosis induction while minimizing systemic toxicity. Cuproptosis represents a newly characterized death mechanism triggered by copper-dependent mitochondrial protein aggregation, distinct from apoptosis or ferroptosis¹⁰⁷. Lysosome-targeted copper nanomaterials confine copper release to malignant cells, bypassing systemic toxicity⁹⁹. Intralysosomal copper ions disrupt iron-sulfur cluster proteins and induce proteotoxic stress through anomalous oligomerization of tricarboxylic acid cycle components, leading to mitochondrial damage. Copper-loaded nanoparticles further catalyze ROS generation via oxidative reactions, exploiting cancer cells’ altered copper homeostasis to overcome apoptosis resistance. This multipronged attack targets malignancies resistant to conventional therapies¹⁰⁸.

Liu et al.³⁴ developed polyvinylpyrrolidone-modified copper-gallic acid complex nano-boosters (CuGA) to enhance antitumor immunotherapy by inducing lysosomal-mitochondrial cascade damage. The CuGA nano-boosters selectively sequestered endogenous iron within tumor cell lysosomes via an ion-exchange reaction, forming a bimetallic nanozyme Cu(Fe)GA in situ. This process disrupted lysosomal integrity, leading to proton leakage and intracellular acidification. Concurrently, the reaction triggered the release of Cu⁺/²⁺ and dysregulated other essential metals. The liberated Cu ⁺ subsequently targeted mitochondria, impairing the tricarboxylic acid cycle by inducing oligomerization of lipoylated DLAT and downregulating the iron-sulfur cluster proteins FDX1. This ultimately resulted in cuproptosis. This lysosomal damage and mitochondrial dysfunction further activated caspase-3/GSDME-dependent pyroptosis. Notably, the pyroptosis induced by CuGA nano-boosters is primarily driven by Cu-dependent cuproptosis, rather than by overloaded Ca²⁺ or ROS. In vivo, this dual cell death mechanism not only directly kills tumor cells but also stimulates potent anti-tumor immunity, characterized by enhanced DCs maturation and cytotoxic T cell infiltration, effectively suppressing primary tumor growth and metastasis. This work establishes a conceptual framework for designing nanotherapeutics that exploit cuproptosis to initiate lysosomal-mitochondrial cascade disruption, providing a powerful strategy to enhance immunotherapy.

3.2.2. Ferroptosis induction

Ferroptosis is particularly susceptible to induction via lysosomal targeting due to the organelle's role in iron storage and redox metabolism. Nanomaterials can orchestrate ferroptosis by disrupting multiple protective mechanisms within the lysosomal compartment. Lysosomal iron pools and lipid peroxidation dynamics make ferroptosis uniquely inducible via organelle targeting¹⁰⁹. Nanoparticles deplete GSH, inhibit GPX4, or generate lipid ROS within lysosomes to initiate ferroptotic cascades characterized by iron-dependent accumulation of lipid peroxides¹¹⁰. Lysosomal rupture releases iron catalysts that amplify peroxidation chain reactions through the Fenton reaction, resulting in extensive membrane damage. As cancer cells exhibit heightened iron requirements and lipid metabolism dysregulation, lysosome-triggered ferroptosis provides a metabolic Achilles' heel for therapeutic exploitation, being regulated by intracellular iron, lipid, and GSH metabolism¹¹¹.

Pei et al.³⁵ developed poly(ethylene glycol)-modified vanadium disulfide nanosheets (VS₂-PEG) that exploit tumor GSH depletion to trigger H₂S release and vanadate generation for immunotherapy enhancement. The nanosheets underwent GSH-responsive degradation within tumor cells, releasing H₂S which induced lysosomal acidification and subsequent osmotic pressure elevation. This process facilitated lysosomal escape of the nanoparticles and disrupted lysosomal integrity. Concurrently, H₂S impaired mitochondrial function by collapsing the membrane potential, reducing ATP synthesis. The degradation products generated high-valent vanadate ions, which inhibited Na⁺/K⁺-ATPase activity, causing potassium efflux and NLRP3 inflammasome-mediated IL-1β release. VS₂-PEG mediates ferroptosis by depleting GSH, inducing oxidative damage, and inactivating GPX4. Consequently, the treatment reversed immunosuppression by enhancing DCs maturation, cytotoxic T cell infiltration, and M1 macrophage polarization. When combined with α-PD-1, VS₂-PEG amplified systemic antitumor immunity, significantly suppressing primary and metastatic tumor growth. This demonstrates how lysosomally-triggered gas release can work together with ferroptosis to enhance immunotherapy.

Similarly, Zhi et al.³⁶ fabricated functional nucleic acid-engineered bio-barcode nanoplatforms (ZnO@BBCs) for targeted combinatorial therapy of resistant cancer. The system employed platinum (IV) prodrugs covalently linking AS1411 aptamers and DNAzymes to form three-dimensional scaffolds, encapsulating ZnO nanoparticles via electrostatic interactions. The multivalent AS1411 aptamers enabled specific uptake into resistant cells. Following endocytosis, acidic lysosomal environments dissolved ZnO nanoparticles into Zn²⁺. This dissolution triggered a proton sponge effect, facilitating lysosomal escape into the cytoplasm. Subsequently, overexpressed GSH reduced Pt(IV) prodrugs to active Pt(II) species for chemotherapy while releasing DNAzymes. The Zn²⁺ served dual roles: acting as cofactors for DNAzymes to cleave Egr-1 mRNA and generating ROS. Concurrent GSH depletion downregulated GPX4, amplifying oxidative stress and lipid peroxidation to induce ferroptosis. This multimodal approach, integrating chemotherapy, gene therapy, ROS amplification, and ferroptosis induction, synergistically reversed MDR and potentiated tumor suppression in vitro and in vivo.

In another study, Hou et al.³⁷ developed a pH/GSH-responsive nanoparticle system (PC(coBP)Ca_(Er+1M + Yov + Nko)) for the targeted treatment of triple-negative breast cancer, with a focus on CD24-overexpressing cells that dominate tumors and exhibit chemoresistance. The system employed CD24 aptamer-functionalized nanoparticles encapsulating three key components: the ferroptosis agonist erastin, CRISPR-Cas9 plasmids for NF2 knockout and YAP overexpression, and pH-sensitive 1-2M2ge. Tumor cells reside in an acidic microenvironment, and their lysosomes maintain a notably more acidic pH than those in normal cells. Upon receptor-mediated endocytosis into CD24^high cells, acidic lysosomal environments triggered 1-2M2ge decomposition to generate CO₂, inducing lysosomal rupture and escape. Concurrently, elevated intracellular GSH cleaves disulfide bonds in the nanoparticle matrix, enabling the release of erastin and the plasmids in a burst. The released plasmids then inhibited NF2 and overexpressed YAP, thereby suppressing FSP1 and downregulating CD24 expression. This dual action promoted ferroptosis via FSP1 inhibition and enhanced tumor-associated macrophage phagocytosis by blocking CD24/Siglec-10 “don't eat me” interactions. The nanoparticle system demonstrated specific tumor targeting in vivo, and synergistically suppressed tumor growth by inducing ferroptosis and promoting phagocytosis.

3.2.3. Apoptosis/paraptosis induction

While novel cell death pathways offer promising alternatives, the classic apoptotic pathway remains a critical target. Lysosome-targeted nanomaterials can initiate apoptosis through controlled release of cathepsins, as well as induce paraptosis, a caspase-independent cell death mode characterized by cytoplasmic vacuolation, resulting from sustained lysosomal stress. Lysosomal cathepsins activate both extrinsic and intrinsic apoptotic pathways by initiating caspase cascades¹¹². Nanomaterials inducing controlled LMP initiate apoptosis while avoiding inflammatory necrosis. Alternatively, progressive lysosomal dysfunction causes ER stress and mitochondrial calcium overload, leading to vacuolization-dependent paraptosis^113,114. This includes cytosolic ROS elevation, mitochondrial depolarization, and ER stress, which prevents secondary necrosis¹¹⁵. These controlled death modalities support immunogenic clearance, making them preferable for combinatorial regimens in targeting tumor cell vulnerabilities.

Translating these principles into therapeutic designs, several innovative nanoplatforms have been developed. Jiang et al.³⁹ developed a cRGD-targeted biomimetic nanocapsule (DNAzyme biocapsule) for treating breast cancer. The system encapsulates polyethylenimine-complexed DNAzyme within a Mn²⁺/Zn²⁺-coordinated inositol hexaphosphate (IP6) shell. Following tumor cell uptake, the acidic lysosomal environment triggers degradation of the nanocapsule, simultaneously releasing the DNAzyme and abundant Mn²⁺/Zn²⁺ cofactors essential for its catalytic activity (Fig. 6³⁹). The component facilitates DNAzyme escape from the lysosome into the cytosol. The released DNAzyme cleaves EGR-1 mRNA, while IP6 independently downregulates Bcl-2 expression, synergistically inducing tumor cell apoptosis. DNAzyme biocapsule significantly promotes the cell apoptosis rates (∼76.8%) of MCF-7 cells. Both in vitro and in vivo evaluations demonstrated significant suppression of EGR-1 and Bcl-2 proteins, potent antitumor efficacy against primary tumors, and effective inhibition of pulmonary metastasis, highlighting the critical role of lysosomal activation in enabling this self-sufficient gene therapy.

Figure 6.

(A) Therapeutic mechanism of the DNAzyme biocapsule for DNAzyme-mediated gene therapy. (B) Fluorescence images and corresponding lysosomal colocalization scatter plots of MCF-7 cells that were incubated with 50 nmol/L Cy3-labelled DNAzyme biocapsules for 1, 3, and 9 h. Lysosomes were stained with LysoTracker Green (green). (C, D) Western blot analysis of Bcl-2 and EGR-1 protein expression in MCF-7 cells after various treatments. (E) Flow cytometric analysis of apoptosis in MCF-7 cells treated for 48 h with PBS or DNAzyme formulations (50 nmol/L equivalent). (Adapted with permission from Ref. 39).

Beyond such gene-targeted systems, other lysosome-focused nanoplatforms employ distinct mechanisms to induce coordinated cell death. Guo et al.³⁸ developed a disulfiram-loaded Ca²⁺/Cu²⁺ nano-trap (DM-CaCO₃@L-PEG NPs) that degrades in acidic lysosomes, releasing components that induce mitochondrial Ca²⁺ overload, Fenton-like reactions, and toxic CuET formation, effectively triggering both paraptosis and apoptosis with significant antitumor efficacy. Li et al.⁴⁰ designed a H₂O₂-driven Janus gold nanorod-platinum nanomotor (JAuNR-Pt) that utilizes self-propulsion to enhance cellular uptake and lysosomal escape, enabling sustained Pt²⁺ release in TME to cause DNA damage and apoptosis, along with improved deep-tumor penetration and effective therapy with low toxicity. Lin et al.⁴¹ demonstrated that the autophagy receptor SQSTM1/p62 plays a critical role in mediating lysosomal delivery of albumin-bound paclitaxel nanoparticles (Nab-PTX), facilitating drug release via the autophagosome-lysosome pathway and inducing mitotic catastrophe and caspase-3-dependent apoptosis, with SQSTM1 expression levels correlated to tumor progression and patient prognosis. In summary, these versatile nanoplatforms exploit the lysosome beyond a drug-release switch to modulate core cellular processes, enabling the precise induction of coordinated apoptosis and paraptosis for advanced cancer therapy.

3.2.4. Pyroptosis induction

Lysosome-targeted nanomaterials are uniquely positioned to trigger this highly inflammatory PCD by releasing lysosomal contents that activate inflammasome complexes^116,117. Pyroptosis links lysosomal damage to antitumor immunity via cytokine and DAMP release¹¹⁸. Lysosome-targeted nanoparticles activate NLRP3 inflammasomes via cathepsin B release or potassium efflux, resulting in the cleavage of gasdermins to form membrane pores¹¹². This releases IL-1β and DAMPs that recruit DCs and T cells, enhancing ICD and antigen presentation. Converting immunologically silent cell death into pyroptosis addresses key limitations of conventional chemotherapy by promoting T cell proliferation and infiltration, thereby priming tumors for immune attack.

Niu et al.⁴² developed a hexahistidine-metal assembly (HmA) nanocarrier for the combined delivery of nigericin (Nig) and decitabine (DAC). This (Nig + DAC)@HmA system demonstrated efficient cellular uptake via endocytosis and subsequent lysosomal escape within 8 h, facilitating the release of drugs into the cytoplasm while protecting payloads from lysosomal degradation. DAC upregulated GSDMD expression through DNA demethylation, while Nig activated the NLRP3 inflammasome and caspase-1. This dual action synergistically induced pyroptosis in tumor cells, characterized by GSDMD cleavage and pore formation. The nanocarrier enhanced tumor accumulation in vivo and significantly suppressed tumor growth by triggering ICD. This process reprogrammed tumor-associated macrophages toward the M1 phenotype and stimulated systemic antitumor immunity, with minimal hemolysis and negligible systemic toxicity. Thanks to its ability to accumulate effectively in tumors, low immunogenicity, rapid endocytosis and lysosomal escape, the HmA is a promising drug delivery vector for overcoming tumor resistance.

3.3. Remodeling the tumor immune microenvironment

The therapeutic impact of lysosome-targeted nanomaterials is not confined to the direct killing of cancer cells. A pivotal consequence of lysosomal disruption is the release of DAMPs and other immunostimulatory signals that can fundamentally reshape the tumor immune microenvironment, turning “cold” tumors “hot”. Lysosomal targeting extends beyond direct cancer cell killing to DAMP-mediated immunomodulation, reshaping TME and potentiating systemic immunity. This dual functionality addresses immune evasion in cancer therapy. By releasing DAMPs through lysosomal disruption, nanomaterials convert immunologically cold tumors into hot ones, enhancing immune infiltration¹¹⁹. Furthermore, lysosomal modulation reprograms tumor-associated macrophages and DCs toward immunostimulatory phenotypes, extending therapeutic efficacy and enabling sustained immunity¹²⁰.

3.3.1. STING pathway-mediated innate immune activation

The release of lysosomal contents into the cytosol potently activates the cGAS–STING pathway, converting organelle damage into a potent pro-inflammatory signal that reshapes the tumor immune microenvironment. Cytosolic dsDNA released during lysosomal damage activates the cGAS–STING pathway, a key mechanism for triggering innate immune responses^121,122. Nanoparticles designed to stimulate lysosomal rupture can deliver cyclic dinucleotides or self-generate nucleic acid debris, hyperactivating STING signaling to promote type I interferon production¹²². This activation enhances DCs maturation and CD8⁺ T cell priming, reshaping the immunosuppressive microenvironment into a more immunogenic state¹²³. STING-activating strategies are shown to convert immunologically inert tumors into vaccine-like microenvironments by promoting CD8 T cell infiltration and enhancing interferon responses.

The DC-derived nanovaccine Si9GM, formulated by coating bone marrow DCs membranes conjugated with a cDC1-targeting αCLEC9A antibody and OVA_257–264 peptide onto dendrimer-like porous silica nanoparticles co-loaded with αCLEC9A-OVA_257–264 conjugates and the STING agonist 2′,3′-cGAMP, selectively targets type 1 conventional dendritic cells (cDC1s)⁴⁶. Si9GM facilitates lysosomal escape, promotes potent STING pathway activation and type I interferon production within cDC1s, and enhances antigen cross-presentation. This leads to significant expansion of cytotoxic CD8⁺ T cells, reduction in Tregs, and polarization towards M1 macrophages. Furthermore, Si9GM synergizes with αPD-1 immune checkpoint blockade to suppress primary tumor growth and inhibit lung metastasis in B16-OVA melanoma models, while demonstrating minimal systemic toxicity. This nanovaccine is designed to achieve effective cancer immunotherapy by selectively activating the STING pathway.

Zhang et al.⁴⁷ developed mannose-modified stearic acid-grafted chitosan (M-CS-SA) nano-micelles for targeted antitumor immunotherapy. These micelles specifically targeted DCs via mannose receptors and demonstrated efficient lysosomal escape. Once internalized, M-CS-SA activated the cGAS–STING signaling pathway by inducing mitochondrial ROS generation and cytosolic DNA sensing, leading to IFN-γ production and DC maturation. Crucially, M-CS-SA effectively adsorbed tumor-associated antigens released by oxaliplatin-induced ICD, forming an in vivo autologous tumor vaccine. In a murine 4T1 model, the sequential administration of oxaliplatin followed by M-CS-SA synergistically amplified antitumor immunity. This combination achieved a tumor inhibition rate exceeding 76%, significantly enhanced CD3⁺ CD8⁺ T cell infiltration within tumors, increased pro-inflammatory cytokine (TNF-α, IFN-γ) secretion, and activated immune cells in lymph nodes. This demonstrates potent efficacy with reduced systemic toxicity.

3.3.2. Synergistic enhancement via PD-1/PD-L1 axis disruption

Lysosome-targeted nanomaterials offer innovative strategies to directly degrade PD-L1 or block its function, thereby synergizing with ICD inducers to overcome immunosuppression. Disruption of the PD-1/PD-L1 axis can overcome immunosuppression by modulating immune checkpoint signaling¹²⁴. PD-L1 expression is regulated by mechanisms such as SRC-1-mediated stabilization via inhibition of proteasome-dependent degradation, which inhibits PD-L1 turnover and contributes to immune evasion¹²⁵. Nanoparticle-based approaches induce permanent PD-L1 removal, preventing compensatory upregulation, and when combined with ICD inducers, they reverse T cell exhaustion¹²⁶. This synergistic approach enhances the efficacy of checkpoint inhibitors without significantly increasing autoimmune risks, particularly by reactivating tumor-reactive CD8 T cells in the microenvironment^125,127.

Xing et al.⁴⁸ developed a pH-responsive bifunctional lysosome-targeted chimera (LYTAC) nanoplatform (NLTC-BMS/CAT-PDA) for tumor-selective protein degradation and enhanced immunotherapy. This system featured a protein nanocapsule core functionalized with ligands targeting CI-M6PR and PD-L1, encapsulated catalase, and was coated with a detachable PEG shell. Following intravenous administration, the PEG layer prolonged circulation and prevented off-target activation. In an acidic TME, PEG detachment exposed the core, enabling simultaneous CI-M6PR-mediated endocytosis and lysosomal degradation of membrane PD-L1. At the same time, CAT catalyzed the decomposition of tumor-associated H₂O₂ into O₂ to alleviate immunosuppression. In melanoma-bearing mice, NLTC-BMS/CAT-PDA achieved marked tumor suppression and significantly inhibited metastasis. This effect was attributed to enhanced CD8⁺ T cell infiltration, reduced levels of myeloid-derived suppressor cells and regulatory T cells, increased pro-inflammatory cytokines (IFN-γ, TNF-α), and induction of memory T cells compared to controls. By promoting lysosomal degradation of cancer cell PD-L1, this strategy reverses immunosuppression and achieves potent immunotherapy, significantly suppressing tumor growth, recurrence, and metastasis.

Coincidentally, Lu et al.⁴⁹ developed a cancer cell-targeted molecularly imprinted lysosomal nanodegrader (MILND) designed to enhance cancer immunotherapy. The MILND was synthesized using the N-terminal epitope of PD-L1 as an imprinting template via a boronate affinity-anchored oriented surface imprinting approach. This design enabled the MILND to specifically bind PD-L1 overexpressed on tumor cells, promoting cellular uptake. Following internalization, the MILND facilitated the transport of PD-L1 into lysosomes for degradation, effectively downregulating PD-L1 expression on the tumor cell surface. Consequently, this degradation blocked the PD-1/PD-L1 signaling pathway, leading to the activation of T cell-mediated immune responses and triggering a sustained antitumor effect. In vivo evaluations in xenograft tumor models demonstrated that the MILND effectively accumulated at tumor sites and significantly inhibited tumor growth without inducing obvious side effects. The MILND presents a promising strategy for boosting immune checkpoint blockade therapy and offers insights for the development of nanomedicines that target the PD-1/PD-L1 axis.

3.3.3. Immunomodulation via JAK–STAT signaling network

Beyond direct checkpoint disruption, broader immunomodulation can be achieved by targeting key signaling networks such as JAK–STAT. Nanomaterials that modulate this pathway can reprogram myeloid cell function and enhance antigen presentation, creating a more favorable context for immune attack¹²⁸. JAK–STAT signaling is a central regulator of immune responses, with dysregulation commonly observed in TME¹²⁹. Nanoparticles that modulate cytokine signaling, such as by co-delivering IFN-γ and lysosomotropic agents, can amplify STAT1 phosphorylation and prolong cytokine half-life. This amplification reprograms myeloid cells, improves antigen presentation, and overcomes resistance to therapies like radiotherapy¹³⁰. Additionally, disruption of JAK–STAT pathways has been linked to enhanced cytotoxicity of CD8 T cells and reduced PD-L1 expression, facilitating tumor suppression by mitigating immunosuppressive signals.

Yan et al.⁵⁰ developed Nano-IFNγ/Zole, a zoledronate-mineralized nanoparticle loaded with IFNγ and dispersed in alginate gel for local administration during incomplete radiofrequency ablation (iRFA) surgery. This system enabled sustained retention of IFNγ and zoledronate within residual tumor tissue. Zoledronate inhibited the mevalonate pathway, blocking isoprene modification of Rab GTPases, which impaired vesicular trafficking, reduced lysosomal acidification, and activated TFEB. Concurrently, IFNγ activated the JAK–STAT1 signaling pathway (Fig. 7⁵⁰). The synergistic action of TFEB and STAT1 reprogrammed tumor-associated macrophages from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, remodeling TIME induced by iRFA. In murine models of colorectal cancer, a single administration of Nano-IFNγ/Zole significantly suppressed residual tumor growth and metastasis post-iRFA. Overall, Nano-IFNγ/Zole reduced lysosomal acidification to activate the TFEB pathway. This activation, in conjunction with JAK–STAT1 signaling, repolarized tumor-associated macrophages from the M2 to the M1 phenotype. This remodeling of the iRFA-induced immunosuppressive TME restored sensitivity to ICIs.

Figure 7.

(A) Schematic illustration of the preparation of Nano-IFNγ/Zole and its application to remodel the immunosuppressive tumor immune microenvironment induced by iRFA. (B) qRT-PCR analysis of M1-and M2-type gene expression in sorted tumor-associated macrophages after indicated treatments (n = 4). (C) Representative fluorescence images and quantification of lysosome acidification in M2-polarized bone marrow-derived macrophages (M2-BMDMs) after treatment (n = 30–31 cells; scale bar: 50 μm). (D) STAT1, pSTAT1, and TFEB expression in M2-BMDMs after treatment. All statistical data are presented as mean ± SD; data were analysed using two-tailed unpaired t-tests; ns: not significant; ∗P < 0.05, ∗∗∗P < 0.001. (Adapted with permission from Ref. 50).

4. Synergistic therapeutic modalities leveraging lysosomal targeting

The true potential of lysosome-targeted is fully realized when integrated with other therapeutic modalities. This section highlights advanced combination strategies where lysosomal intervention acts as a powerful sensitizer or amplifier, unlocking new dimensions of efficacy in cancer treatment by overcoming common resistance mechanisms and creating synthetic lethality. Lysosomal targeting amplifies established cancer therapies by overcoming resistance mechanisms rooted in drug sequestration, pH gradients, or compensatory survival pathways. Nanomaterials that co-deliver lysosomotropic agents with chemo/radiotherapeutics or energy-disrupting compounds create synthetic lethality in tumors, integrating with modalities such as photothermal and photodynamic therapies to enhance efficacy^131,132. This section highlights combinations where lysosomal intervention unlocks new dimensions of efficacy, drawing from research on targeting lysosomal membranes, acidity, and cathepsins for therapeutic advantage¹³³. Synergistic approaches exploit lysosomal vulnerabilities to improve outcomes in multimodal treatments^134,135.

4.1. Metabolism-targeted synergistic therapy

Cancer cells exhibit a rewired metabolism with heightened dependencies on specific nutrients and pathways. Lysosomes, as central metabolic hubs, represent ideal targets for synergistic strategies that simultaneously disrupt nutrient sensing, energy production, and recycling processes, pushing cancer cells into metabolic crisis. Metabolism-targeted synergistic approaches exploit cancer-specific metabolic vulnerabilities by combining lysosomal disruption with metabolic pathway inhibition. This strategy counters metabolic adaptability, a key resistance mechanism to monotherapies¹³⁶. As critical metabolic hubs, lysosomes coordinate nutrient recycling via autophagy and macropinocytosis, processes hyperactivated in nutrient-scarce TME to sustain biosynthesis¹³⁷. Concurrently targeting lysosomal function (such as blocking cathepsins) and cancer-enriched metabolic pathways (including glycolysis, glutaminolysis, or lipid synthesis) creates synergistic lethality: lysosomal impairment deprives cells of recycled substrates, while metabolic inhibitors cut off de novo supply, selectively compromising cancer cells reliant on both pathways. Normal tissues with lower metabolic demands and alternative energy sources remain spared due to metabolic heterogeneity.

4.1.1. Chemodynamic therapy (CDT)

The acidic and iron-rich environment of the lysosome provides ideal conditions for CDT, wherein nanomaterials catalyze Fenton-like reactions to generate highly cytotoxic hydroxyl radicals locally. Lysosomal iron pools and acidity provide ideal conditions for Fenton reactions, enabling ROS generation that bypasses penetration limitations of traditional therapies¹³⁸. Nanoparticles that concentrate copper or iron-based nanozymes within lysosomes generate localized ROS storms, minimizing off-target oxidation while exploiting cancer cells’ metallic vulnerabilities. This lysosome-confined CDT synergizes with therapies that deplete reducing agents like GSH, utilizing transition-metal-based catalysts to enhance cytotoxic effects in a tumor-selective manner. Examples include biodegradable nanomaterials facilitating CDT-chemotherapy combinations for deeper tissue penetration¹³⁹.

Hu et al.⁵¹ developed an NIR-actuated Janus nanomotor (ZnO₂@PDA-Fe, Z@P-F) by asymmetrically coating ZnO₂ with polydopamine (PDA) and chelating Fe²⁺. Under NIR irradiation, the asymmetric PDA layer generated a thermal gradient, propelling the nanomotor via self-thermophoresis, enhancing tumor penetration and lysosomal escape. Concurrently, ZnO₂ decomposition supplied H₂O₂ in an acidic TME, while NIR-triggered Fe²⁺ release synergistically amplified ROS generation via the Fenton reaction. This dual mechanism depleted GSH, downregulated GPX4 and SLC7A11, and induced lipid peroxidation, promoting ferroptosis. In 4T1 tumor-bearing mice, Z@P-F plus NIR irradiation achieved profound tumor control, demonstrating significant efficacy for synergistic CDT. This study proposes a therapeutic strategy that utilizes in situ self-supplied ROS for localized tumor treatment, offering a promising platform to enhance CDT efficacy in solid tumors with clinical translational potential.

4.1.2. Glucose deprivation therapy

Cancer cells exhibit heightened metabolic demands, particularly for glucose¹⁴⁰. Lysosome-targeted metabolic interference strategies can exploit this vulnerability by depleting intracellular glucose or generating non-metabolizable analogs, inducing an energy crisis specifically in tumor cells. Cancer cells’ lysosomal hyperactivity creates dependence on glucose for glycosylation and autophagy, which can be disrupted through starvation therapy approaches. Nanoparticles depleting intralysosomal glucose or generating non-metabolizable analogs induce energy collapse, targeting metabolic pathways like glycolysis to induce synthetic lethality. When combined with lysosomal alkalinization that blocks autophagy-dependent nutrient recycling, this strategy exploits the cancer-specific reliance on lysosomal functions for survival¹⁴¹. Innovations in nanotheranostics, such as those enabling imaging-guided therapy, further refine glucose deprivation for hypoxic tumors¹⁴².

Yue et al.⁵² developed an albumin-based nanoparticle (AbCholB) that incorporates phenylboronic acid-modified cholesterol (CholB), exploiting the heightened metabolic demands of cancer cells. Malignant cells internalize AbCholB via LDL receptors, transporting it to lysosomes where CholB reacts with intracellular glucose to form glucosyl-cholesterol analogs (GlcCholB). These non-degradable metabolites accumulate as microcrystals, inducing lysosomal storage disorder-like pathology characterized by organelle swelling, glycosphingolipid accumulation, and impaired autophagic flux. Crucially, GlcCholB accumulation disrupts nutrient sensing by inhibiting mTOR recruitment to lysosomes and suppressing glucose/cholesterol metabolism, ultimately depleting cellular ATP. The glucose-dependent mechanism selectively targets cancer cells due to their elevated glucose uptake, sparing normal cells with lower metabolic demands. In mouse 4T1 models, AbCholB strongly suppressed primary tumor growth and reduced pulmonary metastases without altering systemic glucose or lipid levels.

In parallel to glucose competition strategies, other lysosome-targeted approaches have been developed to enhance combined glucose deprivation therapy. Wang et al.⁵³ developed GalNAc-modified peptide nanospheres for lysosome-targeted degradation of CD24, reversing macrophage immunosuppression. When co-loaded with glucose oxidase, the system combined lysosomal degradation with glucose depletion to suppress tumor growth. In another approach, Feng et al.⁵⁵ designed calcium-doped polydopamine nanoparticles (839/CG) that released calcium to disrupt autophagosome-lysosome fusion. This disruption, combined with glutamine depletion-induced mTOR inhibition, created a self-amplifying cycle of drug propagation, enhancing tumor penetration and suppressing metastasis. Together, these advances underscore the potential of combining glucose deprivation therapy with lysosome-targeted agents to induce synergistic metabolic stress and antitumor effects, providing a multifaceted strategy against aggressive and treatment-resistant cancers.

4.2. External field-responsive synergistic therapy

Spatiotemporal control is a coveted goal in cancer therapy to maximize on-target effects and minimize systemic toxicity. The integration of lysosome-targeted with external field-responsive nanomaterials allows for precise, externally triggered activation of therapeutic effects specifically within the tumor, offering a high degree of control over treatment delivery and potency. External field-responsive nanomaterials enable spatiotemporal control of lysosomal targeting through tumor-selective accumulation, confining therapeutic activation to minimize systemic toxicity and address off-target effects. This advanced strategy addresses the persistent challenge of off-target toxicity in cancer treatment by confining therapeutic activity to defined anatomical locations. By engineering nanomaterials responsive to non-invasive external stimuli such as US, researchers can trigger lysosomal disruption precisely when and where needed via mechanisms like sonocatalysis¹⁴³. This controlled activation not only enhances therapeutic efficacy through synergistic mechanisms but also significantly improves the safety profile by reducing exposure of healthy tissues to potentially damaging agents.

4.2.1. Sonodynamic therapy

SDT leverages ultrasound to activate sonosensitizers, offering superior tissue penetration. By localizing sonosensitizers within lysosomes, SDT achieves spatially controlled organelle disruption effective for deep-seated tumors. Lysosome-localized sonosensitizers generate ROS upon US irradiation, achieving spatiotemporally controlled LMP for deep-seated tumors. Nanoparticles that enhance cavitation within acidic organelles amplify mechanical disruption while releasing sequestered drugs, overcoming limitations in tissue penetration associated with light-dependent methods¹⁴⁴. This approach leverages biodegradable nanoplatforms to integrate SDT with photothermal or chemodynamic synergies, enhancing efficacy in multimodal contexts¹⁴⁵.

Chen et al.⁵⁶ developed an acid-activated, biodegradable nanosonosensitizer (CaO₂@PCN) by coating CaO₂ cores with porphyrinic metal-organic frameworks (PCN-224). Upon reaching tumor cells, the nanoparticles were internalized and trafficked to lysosomes. Within the acidic lysosomal environment, the PCN-224 shell degraded sequentially, exposing the CaO₂ core to hydrolysis. This releases Ca²⁺ and H₂O₂, inducing intracellular calcium overload. Concurrently, US irradiation activated the PCN component to generate transient ROS, which further disrupted calcium channels. The calcium overload triggered mitochondrial dysfunction and persistent ROS production via ion interference therapy. This cascade-initiated by lysosomal degradation and amplified by ultrasound-synergized with SDT, achieving potent tumor suppression through sustained oxidative stress while maintaining favorable biosafety due to pH-responsive biodegradability.

4.2.2. Photoirradiation therapy

Light-based therapies benefit greatly from lysosomal targeting as the confined space amplifies oxidative damage. Light can also trigger precise nanomaterial transformations within lysosomes, leading to physical organelle disruption. Lysosomal confinement of photosensitizers prevents off-target phototoxicity while concentrating ROS generation in an acidic environment, where pH-activatable properties enhance tumor selectivity. Light-triggered lysosomal rupture releases immunogenic contents, marrying direct killing with immune activation for phototherapy applications. Nanoparticles, including those based on FePt or Mn-complexes, prolong photosensitizer retention in lysosomes to increase lethality per photon activation while sparing normal tissues^146,147. This therapy integrates with MRI and multimodal imaging for precision in lysosome-specific irradiation.

Zhang et al.⁵⁷ developed an alkaline phosphatase (ALP)-responsive peptide precursor (C1) that selectively targets lysosomes in ALP-overexpressing uveal melanoma cells. Upon contact with tumor cells, C1 undergoes ALP-catalyzed dephosphorylation to form C2, which is endocytosed and accumulates in lysosomes. Subsequent light irradiation cleaves C2 into two components (C3 and C4), which self-assemble into nanofibrils and nanorods, respectively. These nanostructures form stable double-network assemblies via interfacial interactions in the acidic lysosomal environment. This in situ assembly disrupts lysosomal membrane integrity, triggering LMP, cathepsin B release, mitochondrial damage, and elevated ROS, ultimately inducing tumor cell death. In vivo, C1 combined with localized two-photon irradiation significantly suppressed tumor growth in xenograft models with minimal systemic toxicity, outperforming untargeted controls and achieving the same efficacy as DOX without causing organ damage. These findings provide valuable insights into tumor-cell specific lysosome-targeted therapeutic agents.

4.2.3. Photothermal therapy (PTT)

PTT converts light energy into heat, and when combined with lysosomal targeting, this heat can be confined to induce vapor nanobubble formation and physical rupture. This approach allows for lower therapeutic doses and reduced collateral damage. Photothermal nanoparticles (such as CuS/MnO or FePt/BP-PEI-FA nanoplatforms) accumulating in lysosomes convert light to heat, inducing vapor nanobubble formation that physically disrupts membranes¹⁴⁸. Mild hyperthermia concurrently sensitizes lysosomes to permeabilization, enabling lower therapeutic doses for reduced collateral damage. Synergistic combinations with CDT, PDT, or immunotherapy amplify effects, such as in nanomaterials generating heat-responsive ICD^149,150. Innovations in hybrid nanostructures enhance tumor-targeting for PTT-dominated synergistic treatments.

Fan et al.⁵⁸ developed oligonucleotide-conjugated π–polymer nanoparticles (OCPNs) by grafting Bcl-2 antisense oligonucleotides (ASO) onto an alternating copolymer (PFTQ), after which the particles underwent self-assembly. These nanoparticles demonstrated enhanced NIR-II fluorescence quantum yield compared to PEG-encapsulated counterparts due to reduced π–π stacking. OCPNs exhibited rapid tumor accumulation, leveraging their dense DNA surface for improved tissue penetration. Cellular uptake occurred primarily through caveolae/lipid raft-mediated pathways, facilitating efficient cytoplasmic ASO delivery. Under mild PTT, OCPNs promoted lysosomal escape and synergistic Bcl-2 protein downregulation (Fig. 8). This combined low-temperature PTT and gene therapy achieved 80% tumor suppression in vivo, while maintaining favorable biosafety profiles. Taken together, they have demonstrated a strategy that leverages photothermal-promoted lysosome escape to enhance gene transfection, positioning OCPNs as a promising platform for future biological applications.

Figure 8.

(A) Schematic of PFTQ OCPNs preparation via the self-assembly of PFTQ-g-DNA amphiphilic copolymers. (B) The mechanism of low-temperature PTT-gene therapy mediated by PFTQ_ASOCPNs. (C) Confocal laser scanning microscopy images and fluorescence intensity profiles of A549 cells incubated with PFTQ_ASOCPNs and LysoTracker Green, with and without laser irradiation (0.6 W/cm², 10 min). (D) Representative tumor tissue images. (E) Tumor volume changes in mice across treatments (n = 5). (F) Mean tumor weights on Day 19 post-treatment (n = 5). All statistical data are presented as mean ± SD; data were analysed using two-tailed unpaired t-tests; ∗∗P < 0.01, ∗∗∗P < 0.001. (Adapted with permission from Ref. 58).

In the context of PTT, Zhang et al.⁵⁹ constructed an integrated nanoplatform (Fe₃O₄@BSA-TAFe^Ⅲ) that enables tumor-targeted delivery and lysosomal pH-responsive Fe³⁺ release. This system not only enhances T1-weighted MR imaging but also triggers Fenton reaction-mediated ferroptosis and apoptosis, while concurrently providing PTT and suppressing Hsp70 expression to overcome thermoresistance. Under 808 nm laser irradiation, complete tumor eradication was achieved. In a parallel strategy, Liang et al.⁶⁰ developed a dual-responsive nano-prodrug (DM NPs) activated by esterase and acidic pH. This formulation exhibits augmented photothermal/photodynamic performance and enables simultaneous mitochondrial and lysosomal targeting. The resulting dual-organelle damage efficiently induces caspase-mediated apoptosis upon 660 nm laser irradiation, demonstrating high phototoxicity with minimal dark toxicity. These studies collectively demonstrate that lysosome-targeted strategies enhance PTT efficacy by synergizing with other mechanisms such as ferroptosis and apoptosis, offering important directions for developing highly effective and minimally toxic combination therapies.

4.2.4. Photodynamic therapy

PDT relies on the light-activated production of ROS. Lysosomal targeting enhances PDT by concentrating the photosensitizer and its toxic effects within a membrane-bound compartment, leading to more efficient lysosomal rupture and amplified ICD. Lysosomal PDT generates singlet oxygen within membrane-enclosed spaces, enhancing oxidative damage through confined diffusion to avoid cytoplasmic ROS spread. Nanoparticles (such as metal-containing 2D nanomaterials) prolong photosensitizer retention in lysosomes, increasing lethality per photon exposure and exploiting acidic environments for amplified ROS production. This method synergizes with chemodynamic and immune therapies to induce pyroptosis or ferroptosis in cancer cells, facilitating multifunctional theranostic applications like imaging-guided treatments^151,152.

Lee et al.⁶¹ engineered a self-assembling nanomedicine (CPPD1) by conjugating the hydrophobic photosensitizer Chlorin e6 (Ce6) with a positively charged, cell-penetrating anti-PD-L1 peptide. The amphiphilic CPPD1 conjugate spontaneously formed carrier-free nanoparticles in aqueous solution, exhibiting a positive surface charge that facilitated cellular uptake and tumor accumulation via the enhanced permeability and retention effect. These nanoparticles operated through a dual therapeutic mechanism. They first demonstrated high-affinity binding to PD-L1 on cancer cells, effectively blocking PD-1/PD-L1 interactions while promoting PD-L1 internalization and lysosomal degradation, thereby mitigating immune evasion. Additionally, under 635 nm laser irradiation, CPPD1 generated substantial intracellular ROS, inducing ICD characterized by the release of DAMPs, including calreticulin and HMGB1. In the colorectal cancer model, CPPD1-based PDT significantly suppressed primary tumor growth compared to free Ce6 PDT. Crucially, it also elicited a systemic antitumor immune response, evidenced by enhanced DCs maturation, increased infiltration and activation of tumor-antigen-specific CD8⁺ T cells, and a robust abscopal effect inhibiting the growth of non-irradiated metastatic lung tumors. The study highlights CPPD1 as a promising approach to overcome poor cellular permeability and limited immunogenicity associated with conventional photosensitizers, enabling more effective immunogenic PDT.

Additionally, Wang et al.⁶² developed a tumor-specific activated nano-domino-CRISPR system (TAN) to enhance PDT efficacy through spatiotemporal control. This system co-delivered the photosensitizer Ce6 and a CRISPR/Cas9 plasmid targeting Bcl-2, featuring an enzyme-responsive hyaluronic acid-based shell encapsulating a fluorinated polyethyleneimine/DNA core. When exposed to hyaluronidase-rich TME, TAN initiated a sequential domino activation process. Enzymatic shell shedding first exposed the positively charged core, facilitating cellular entry. Subsequent lysosomal escape enabled nuclear delivery of CRISPR/Cas9 components for targeted Bcl-2 disruption. This genetic intervention depleted intracellular GSH, thereby amplifying oxidative stress from Ce6-generated ROS under 660 nm illumination in superficial tumor regions. Concurrently, Bcl-2 ablation directly activated endogenous apoptosis pathways in deeper tumor tissues beyond the reach of light. In vitro and in vivo studies demonstrated superior cytotoxicity and tumor growth inhibition via this spatial synergy. This design overcomes the limitations of PDT by enhancing superficial oxidative damage and deep-tissue apoptotic induction concurrently.

4.3. Lysosomal enhancement of conventional therapies

Chemotherapy and radiotherapy remain backbone treatments for many cancers, but their efficacy is often limited by drug resistance and tumor cell repair mechanisms. Lysosome-targeted strategies offer powerful solutions to resensitize tumors to these conventional therapies by addressing the root causes of treatment failure, such as lysosomal drug sequestration and therapy-induced protective autophagy. Lysosomal targeting overcomes key resistance mechanisms in conventional cancer therapy by addressing drug sequestration in lysosomes and efflux-mediated drug clearance. This strategy directly counters a primary cause of treatment failure: the inability of therapeutics to reach molecular targets. Through engineered nanomaterials that modulate lysosomal function, such as inducing lysosomal alkalinization to release trapped drugs and co-deliver efflux pump inhibitors, critical resistance barriers are circumvented¹⁰⁴. Synergistically combined with standard therapies, this approach launches multi-pronged attacks on cancer cells while neutralizing their defensive adaptations, potentially restoring therapeutic sensitivity in resistant tumors.

4.3.1. Chemosensitization

A major mechanism of chemotherapy resistance involves the sequestration of weakly basic drugs within lysosomes. Lysosome-targeted nanomaterials can overcome this by co-delivering agents that neutralize lysosomal pH or inhibit drug efflux pumps. Lysosomal sequestration underlies resistance to weakly basic chemotherapeutics, which can be mitigated by nanoparticles co-delivering lysosomotropic agents (chloroquine) or proton pump inhibitors to prevent drug trapping and increase cytosolic availability¹³⁶. This approach rescues the efficacy of anthracyclines, tyrosine kinase inhibitors, and platinum drugs without dose escalation, targeting acidification and membrane permeability for enhanced chemotherapy responsiveness. Recent advancements include nanoparticle-based systems facilitating on-demand release in TME to overcome sequestration¹⁵³.

The drug efflux by P-glycoprotein is the primary contributor of MDR to chemotherapy. Zhu et al.⁶⁶ engineered pH-responsive reversible covalent nanoassemblies through boronate ester bonds between catechol-functionalized polyethylene glycol and phenylboronic acid-modified cholesterol. These nanocarriers were loaded with DOX and the P-glycoprotein inhibitor tariquidar (TQR), using LDL receptor-mediated endocytosis for tumor-targeted delivery. Acidic lysosomal conditions then trigger the disassembly of the nanoassembly, releasing TQR to suppress P-glycoprotein efflux activity and DOX to enhance nuclear accumulation. In multidrug-resistant tumor models, this drug-loaded nanoassemblies (PC-DOX-T) significantly suppressed tumor growth and extended survival compared to free DOX or non-TQR-loaded controls, while reducing systemic toxicity.

In addition, Yang et al.⁶⁷ developed an enzyme-silenced nanosponge (^siHyal1taLRNS_DOX), which comprises a cationic lipid-coated hyaluronic acid-derived polyampholyte core that is loaded with DOX and hyaluronidase-1 (Hyal1)-targeting siRNA, enveloped by a lipoprotein shell decorated with the tumor-homing fusion peptide 4F-tLyP-1. This design leveraged the tumor's pH gradient: the core reversibly swelled in acidic endo/lysosomes to release DOX and shrank in the cytosol or extracellular matrix to reload DOX. Concurrent Hyal1 gene silencing by siRNA protected the nanosponge from enzymatic degradation, significantly prolonging its intratumoral lifespan. This enabled sustained intercellular relay delivery, where the nanosponge was secreted via the Golgi apparatus to reload DOX and infect adjacent cells sequentially. The nanosponge achieved high tumor inhibition rates of 99.1% in tumor spheroids and 80.1% in orthotopic models. Consequently, the system achieved deep tumor penetration, effectively eliminated tumor spheroids, and significantly inhibited orthotopic tumor growth while suppressing metastasis.

4.3.2. Radiosensitization

Radiotherapy efficacy can be limited by protective autophagy. Nanomaterials that disrupt lysosomal function can block this repair mechanism, converting autophagy into a radiosensitizing process. Radiation-induced autophagy protects tumors via damaged organelle clearance; nanoparticles blocking lysosomal function prevent this repair mechanism, converting autophagy into a radiosensitizing process. Concurrently, lysosome-targeted radiosensitizers concentrate metal catalysts at damage sites, enhancing free radical generation during irradiation for therapies like radiotherapy or radiodynamic treatment. This strategy integrates with CDT or ferroptosis to amplify ionizing radiation effects, leveraging iron-based nanomaterials to improve Fenton reaction efficiency at damage foci¹⁵⁴.

Han et al.⁶⁹ developed a cerium vanadate (CeVO₄) nanozyme that exhibits pH-switchable catalytic properties, including potent peroxidase-like activity generating cytotoxic•OH under acidic conditions, and superoxide dismutase-like activity scavenging superoxide anions under neutral conditions. In vitro, the nanozyme demonstrated differential subcellular localization and function in glioblastoma cells versus neuronal cells. In glioblastoma cells, CeVO₄ localizes to lysosomes, where its potent peroxidase activity in an acidic environment induces ROS accumulation, triggering DNA damage and ultimately leading to apoptosis. Conversely, in neuronal cells, it underwent lysosomal escape mediated by the fast endophilin-mediated endocytosis pathway and weak lysosomal repair, subsequently localizing near mitochondria where its superoxide dismutase activity reversed irradiation-induced mitochondrial damage, restored ATP synthesis, and upregulated Bcl-2 expression. In vivo, local administration of CeVO₄ combined with radiotherapy in mouse models significantly suppressed tumor growth while concurrently mitigating radiation-induced brain injury, evidenced by reduced neuronal apoptosis, improved mitochondrial function, normalized exploratory behavior, and diminished cerebral edema. This organelle-specific targeting enabled the achievement of both tumor cytotoxicity and neuroprotection simultaneously.

5. Future perspectives

From the foundational understanding of lysosomes as degradative organelles to their recognition as dynamic signaling hubs, the field has evolved toward sophisticated nanomaterial designs that exploit lysosomal properties with unprecedented precision. These advancements underscore the potential of lysosome-targeted nanomedicines to address unmet clinical needs in oncology, particularly for intractable cancers resistant to traditional therapies. Despite these advances, several challenges impede the clinical translation of lysosome-targeted nanomaterials.

5.1. Addressing tumor heterogeneity via precision phenotyping

Tumor heterogeneity creates substantial translational barriers due to inter- and intra-tumoral variations in core lysosomal characteristics, including acidification potential, hydrolase expression levels, and lysosomal abundance. For instance, pH-responsive nanomaterials show reduced efficacy in tumors with low lysosomal acidification, while enzyme-targeted strategies may better suit tumors with elevated cathepsin expression. However, this heterogeneity also presents an opportunity for precision medicine. The functionality of lysosomal features is highly context-dependent. For example, cathepsin B often promotes invasion in many tumors, while it is associated with a favorable prognosis in certain thyroid cancers. Furthermore, the translocation of LAMP1 and LAMP2 to the plasma membrane to enhance invasiveness is observed in specific cancers such as melanoma and non-small cell lung cancer, but it is not a universal phenomenon. To overcome this variability, future designs must prioritize personalized approaches leveraging cancer-specific lysosomal membrane proteins for selective uptake. This entails designing phenotype-specific nanomedicines, for instance, LAMP1-targeted magnetic nanoparticles for tumors with high LAMP1 membrane expression to induce lysosomal permeabilization under an applied dynamic magnetic field, or developing enzyme-responsive prodrug systems for tumors with elevated cathepsin activity¹⁵⁵. Further exploration of tumor-specific endocytic pathways and biomarkers will enable patient stratification and phenotype-tailored therapies. A robust patient stratification framework guided by a panel of lysosomal biomarkers, including LAMP2A, TRPML1, and cathepsin profiles, is crucial for clinical translation¹⁵⁶.

5.2. Elucidating organelle interplay and resistance mechanisms

The intricate crosstalk between lysosomes and organelles like mitochondria and ER remains poorly understood, obscuring critical molecular thresholds and temporal dynamics governing therapeutic cascades. For example, lysosomes release Ca²⁺ via TRPML1 channels to influence mitochondrial metabolism and cell death pathways, while lysosomal dysfunction can induce mitochondrial stress, activating the NLRP3 inflammasome¹⁵⁷. Compounding this gap, compensatory survival pathways may be upregulated in response to lysosomal stress, such as transcription factor EB-mediated lysosomal biogenesis or enhanced autophagic flux, potentially driving therapeutic resistance¹⁵⁸. Addressing these knowledge deficits requires deeper mechanistic investigation using multi-omics approaches and spatial transcriptomics to map molecular networks linking lysosomal function to emerging cell death pathways such as ferroptosis and pyroptosis. These insights are fundamental for devising rational combination strategies, such as dual-targeting the lysosomal TRPML1 channel and mitochondrial metabolism or developing nano-systems that co-target glucose-regulated protein 78 and lysosomes¹⁵⁹. Such insights are essential for predicting resistance and designing robust intervention strategies.

5.3. Mitigating systemic toxicity and immune dysregulation

Long-term safety concerns persist for lysosome-disrupting strategies, which risk damaging healthy tissues through systemic toxicity or chronic cellular stress. Nanomaterials that induce the “proton sponge effect” risk causing off-target LMP in healthy tissues. Moreover, excessive immune activation, particularly through STING pathway hyper-stimulation, often due to the aberrant release of lysosomal cathepsins, could trigger inflammatory toxicities or autoimmune sequelae. Balancing efficacy with safety necessitates developing immunomodulatory strategies that harness beneficial responses while avoiding pathological inflammation. This can be achieved by developing “smart” nanoplatforms with tumor-selective activation properties, such as systems responsive to microenvironment's distinctive pH or enzymatic conditions, or using functional materials like hybrid-charge nanoparticles or cationic liposomes¹⁶⁰. Rigorous evaluation of off-target effects in complex preclinical models, including humanized mouse models and three-dimensional tumor organoids, is paramount to ensure clinical viability.

5.4. Engineering synergistic systems against therapeutic resistance

The intrinsic heterogeneity of tumors and their capacity for adaptive resistance limit the efficacy of single-pathway lysosomal targeting. To circumvent these limitations, combinatorial approaches exploiting multiple cellular vulnerabilities show strong promise. Preclinical evidence shows that combining lysosomal disruptors with Poly (ADP ribose) polymerase inhibitors yields synergistic efficacy in triple-negative breast cancer models¹⁶¹. Similarly, integrating lysosome-targeted nanomedicines with immune checkpoint inhibitors including anti-PD-1 antibody can concurrently trigger tumor cell death and activate antitumor immunity. Future work should prioritize integrating lysosomal disruption with immunomodulation or metabolic interventions and explore synergies with metabolic interventions targeting pathways such as mTORC1 inhibitors or epigenetic modulators (like HDAC inhibitors). The development of co-delivery nanoplatforms presents a viable strategy for achieving multi-tiered disruption.

5.5. Accelerating translation through technology and adaptive trial design

Translating preclinical findings is hindered by inadequate models recapitulating TME complexities and the lack of biomarkers for patient stratification. Bridging this gap demands leveraging cutting-edge tools: super-resolution microscopy to visualize nanomaterial–lysosome interactions at the nanoscale, and single-cell multi-omics (RNA-seq, mass cytometry) to dissect intratumoral lysosomal heterogeneity. Concurrently, standardized physiologically relevant models must be developed. This includes pioneering sophisticated models such as lysosome-reporter engineered organoids and microfluidic tumor-on-a-chip devices. For clinical implementation, lysosomal biomarkers should guide patient selection, while innovative trials incorporating real-time lysosomal function monitoring using novel molecular probes for parameters such as pH and enzyme activity as pharmacodynamic endpoints could optimize dosing. Adaptive designs combining lysosome-targeted agents with established therapies will accelerate therapeutic validation.

6. Conclusions

The convergence of lysosomal biology and nanomaterial engineering has ushered in a transformative era for cancer therapy, capitalizing on the unique vulnerabilities of tumor cells to achieve precise and potent therapeutic outcomes. This comprehensive review has elucidated how lysosome-targeted nanomaterials can modulate critical lysosomal functions, induce diverse PCD pathways, and synergistically enhance conventional treatments, thereby redefining therapeutic strategies for overcoming cancer resistance.

Several pivotal themes have emerged from this review, highlighting the multifaceted potential of lysosome-targeted nanomaterials. First, the dynamic regulation of lysosomal functions, including acidification, hydrolytic degradation, autophagosome-lysosome fusion, and organellar crosstalk, provides a rich landscape for precision interventions. By leveraging rational nanomaterial designs (like pH-responsive drug release, stimuli-triggered self-assembly, or receptor-targeted LMP), these systems can selectively disrupt cancer cell lysosomal homeostasis while sparing healthy tissues. Second, lysosomal targeting activates cell death processes, such as cuproptosis, ferroptosis, pyroptosis and apoptosis, which exploit cancer-specific metabolic vulnerabilities and induce ICD. This paradigm shift overcomes resistance to apoptosis-centric therapies while stimulating antitumor immunity through DAMP release. Third, synergistic strategies integrating lysosomal targeting with conventional therapies (chemotherapy/radiotherapy), external field-responsive modalities (PTT/PDT/SDT), or immunotherapy demonstrate amplified efficacy. These combinations foster a multifaceted attack on tumors by concurrently disrupting metabolic adaptation, evading drug resistance, and remodeling the immunosuppressive TME.

As our understanding of lysosomal biology deepens and nanomaterial engineering advances, the field is poised to deliver more effective, selective, and personalized cancer therapies. Addressing current challenges, including tumor heterogeneity, organelle interplay, and long-term safety, necessitates interdisciplinary collaboration spanning biology, materials science, and computational modeling. By leveraging advanced technologies and innovative clinical strategies, lysosome-targeted nanomedicines can transition from promising laboratory concepts to impactful clinical solutions. Ultimately, this field holds the potential to redefine cancer treatment paradigms, offering hope for improved outcomes in patients with resistant and difficult-to-treat malignancies.

Author contributions

Hongmei Zheng and Jing Cai proposed the conception and wrote the original draft, Hongmei Zheng, Haipeng Cheng and Jing Cai wrote the main manuscript text, Haipeng Cheng prepared Figure 1, Figure 2, Figure 3 and Namei Li prepared Figure 4, Figure 5, Figure 6, Figure 7, Figure 8. All authors reviewed the manuscript.

Conflicts of interest

The authors declare no conflicts of interest.