Active initiation of plasma membrane rupture represents a promising strategy to disrupt cellular homeostasis and induce cancer cell death. This study proposes phospholipase A1 (PLA1) as a molecular “cell‐puncher” to hydrolyze phospholipids, compromising cancer cell membrane integrity and enabling uncontrolled molecular flux. PLA1 synergistically enhances the tumoradical efficacy of cholesterol oxidases (CODs) and lipoxygenases (LOXs) by liberating their respective substrates, cholesterol, and polyunsaturated fatty acids. When localized within tumors using a thermoresponsive chitosan/β‐glycerol‐phosphate hydrogel, PLA1‐COD or PLA‐LOX enzymatic pairs achieved effective treatment of CT26 murine tumors through cascading plasma membrane rupture and oxidative stress amplification. Furthermore, the hydrogel‐embedded enzyme system functioned as an injectable embolic agent, suppressing orthotopic N1S1 hepatoma in rats via transcatheter arterial enzyme embolization. This work demonstrated an enzyme‐based oncolytic strategy that targets membrane integrity and oxidative stress pathways, showing significant potential for clinical translation in solid tumor management.

RNA-cleaving DNAzymes have emerged as powerful tools for tumor therapy due to their ability to selectively silence disease-related genes through precise RNA cleavage. However, their clinical application faces challenges, including susceptibility to enzymatic degradation and reliance on metal ion cofactors. To overcome these issues, we developed a cross-shaped DNA scaffold for efficient DNAzyme loading, immobilized on MnAl layered double hydroxide nanosheets (MnAl NS) via electrostatic interactions (termed MnAl NS@DNA Cross Probe). This design enhances DNAzyme biostability in physiological environments. After cellular uptake, MnAl NS degrades in the acidic tumor microenvironment, releasing the DNA cross probe and Mn2+ cofactors. MnAl NS@DNA Cross Probe operates via a sequential activation mechanism: first triggered by tumor-overexpressed miRNA-21, which unlocks the DNAzyme structure, then by Mn2+-dependent activation. This dual response enables sensitive miRNA-21 detection while cleaving oncogenic early growth response-1 (EGR-1) mRNA in MCF-7 cells, inducing tumor cell apoptosis. Moreover, MnAl NS serves dual roles: (1) as a proton sponge to neutralize tumor acidity and enhance radiotherapy, and (2) as a Mn2+ source for DNAzyme activation. The system achieves robust gene silencing and radiosensitization, offering anti-tumor efficacy. This work presents a sequentially activated DNAzyme platform with improved stability and promise for clinical cancer treatment.

Metal alkoxides hold promise in catalysis and materials science, but their rapid hydrolysis in aqueous media represents a major limitation for biomedical applications. To harness this intrinsic reactivity therapeutically, we developed a facile ultrasonication-assisted dispersion method to fabricate nanoscale copper ethoxide (CuOEt) with subsequent screening showing their ready dispersion in Lipiodol to form a stable injectable suspension (CuOEt@LPD). Unlike bare CuOEt nanoparticles, which suffered from rapid degradation, a burst release of ethanol, and conversion to copper oxide in water, the CuOEt@LPD formulation utilized a Lipiodol protection strategy to create an effective barrier against water, enabling a sustained release of ethanol. Functionally, the released ethanol upregulated intracellular cytochrome P450 2E1 (CYP2E1), triggering metabolic oxidative stress in hepatocellular carcinoma cells, which acted synergistically with released copper ion-induced cuproptosis, ultimately leading to robust cell death. Furthermore, the Lipiodol dispersant served as a potent radiosensitizer, significantly enhancing the tumor-inhibiting efficacy upon radiotherapy in an H22 murine hepatoma model. Notably, we discovered that this trimodal therapeutic strategy could also initiate a robust antitumor immune response, which established long-lasting immunological memory, thereby effectively suppressing tumor recurrence and metastasis. Our work successfully establishes metal alkoxides nanoparticles as a highly promising class of nanotherapeutic agents for hepatocellular carcinoma treatment.

Tumor-associated inflammation presents a promising therapeutic target, yet it remains insufficiently exploited in current nanomedicine approaches. While inflammation-driven strategies, such as inducing pyroptosis, have the potential to enhance tumor immunity, their limited induction efficiency and poor tumor targeting still pose significant challenges. Herein, we engineer a neutrophil membrane-camouflaged nanoplatform (RC@NMVs) that exploits tumor inflammation to drive reinforcing calcium dyshomeostasis and pyroptotic amplification. This biomimetic system comprises calcium phosphate (CaP) nanoparticles co-loaded with the calcium channel blocker, ruthenium red. Upon internalization by tumor cells, the CaP core dissolves within lysosomes, releasing Ca2 + ions, while ruthenium red inhibits the Ca2+ transporting channels, synergistically elevating intracellular Ca2 + levels. The resulting calcium overload triggers gasdermin-mediated pyroptosis, characterized by the release of damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. The amplified inflammatory microenvironment facilitates the recruitment and tumor accumulation of subsequently administered RC@NMVs. In vivo studies demonstrate enhanced tumor enrichment of RC@NMVs compared to non-inflamed controls, leading to robust pyroptosis and significant tumor inhibition. Moreover, pyroptosis-driven inflammation elicits durable antitumor immune responses, effectively preventing tumor recurrence and metastasis. In general, this work presents a biomimetic strategy that harnesses inflammation-mediated tumor targeting to amplify pyroptosis and immune activation, offering a promising approach for effective cancer therapy.

Photosynthesis is among the most essential biochemical processes on Earth. In nature, cryptophyte algae harness solar energy through specialized light-harvesting complexes. The excitation energy transfer (EET) among these pigments is highly sensitive to the local microenvironment, particularly pH variations resulting from proton gradients induced by fluctuating light intensities. However, the precise mechanisms by which such microenvironmental changes modulate EET in cryptophyte systems remain to be fully elucidated. In this work, we investigate the pH-dependent photophysical behavior and energy transfer dynamics of the light-harvesting complex phycocyanin 645 (PC645). Using pH as a controllable microenvironmental parameter, we performed femtosecond transient absorption (TA) spectroscopy under neutral and acidic conditions to probe ultrafast EET pathways through the selective excitation of specific chromophores. These experimental results are further complemented by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, which characterize the pigment-protein interactions and the local electrostatic environments. Drawing on these insights, we employed coherent modified Redfield theory (CMRT) to simulate the EET dynamics at pH 7 and pH 4. The present study provides experimental and theoretical insights into the adaptive response of PC645 to environmental perturbations and contributes to the understanding of energy-regulatory mechanisms in cryptophyte light-harvesting systems.

DNA-based biomaterials have emerged as powerful platforms for advancing cancer immunotherapy, leveraging their unique programmability, structural precision, and biocompatibility. By enabling rational design at the molecular level, DNA-based biomaterials, including tetrahedra, origami structures, nanorobots, hydrogels, and hybrid nanoparticles, facilitate targeted delivery, immune modulation, and the controlled activation of therapeutic agents. These DNA-engineered biomaterials enhance antigen presentation, regulate immune microenvironments, and alleviate tumor-induced immunosuppression, thereby improving therapeutic efficacy and safety. We summarize the design principles and applications of DNA-based biomaterials in immune regulation, vaccine development, and combination therapy. Moreover, in contrast to prior reviews, we provide a unique synthesis that emphasizes how the programmable spatial organization and physicomechanical properties of DNA architectures can be harnessed to directly engineer immune cell signaling and fate, a key insight for designing next-generation immunotherapies. In addition, we critically discuss the translational challenges, including manufacturing scalability, long-term stability, immune-related safety, and regulatory pathways, that must be addressed to bridge the gap between innovative design and clinical implementation. Finally, we outline future perspectives and strategic directions aimed at advancing these intelligent biomaterials toward safer and more effective cancer immunotherapy.

Cuproptosis, a copper-dependent form of regulated cell death, holds significant promise for oncology, but its therapeutic utility is constrained by the inefficient intratumoral generation of the bioactive Cu+ species. To this end, we report a NIR-II light-activatable thermoelectric nanoreactor (Te@PDA-CuII) designed to achieve spatiotemporally controlled Cu+ production for enhanced cancer therapy. The nanoreactor comprises a tellurium nanorod core, which exhibits a strong thermoelectric effect under 1064 nm light irradiation, coated with a polydopamine (PDA) layer that serves both as a Cu2+ chelation scaffold and an electron-conducting interface. Photothermal activation generates a directional electron flow from the Te core, which is efficiently relayed through the PDA layer to reduce surface-bound Cu2+ to Cu+. Such in situ valence conversion potently triggers cuproptosis via dihydrolipoamide S-acetyltransferase (DLAT) aggregation and Fe─S cluster destabilization. The ensuing cuproptosis initiates immunogenic cell death (ICD), promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration. In orthotopic and metastatic breast cancer models, this thermoelectric-immunological cascade not only eradicates primary tumors but also synergizes with aPD-1 checkpoint blockade to suppress distant metastases and establish durable immune memory. This work establishes a physical energy-driven strategy for precise cuproptosis activation and demonstrates its potential to amplify cancer immunotherapy.

mRNA vaccines hold remarkable promise for cancer immunotherapy, yet current nanoparticle systems face challenges in efficacy, dendritic cell (DC) targeting, and safety. Herein, we report a nanoplatform, Manganese‐Coordinated Polyvalent Aptameric System (COMPASS), enabling targeted co‐delivery of mRNA and Mn 2 + to lymph node dendritic cells (DC) to boost potent antitumor immunity. The COMPASS employed rolling circle amplification to generate single‐stranded DNA scaffolds with multivalent DC‐targeting aptamers and polyT domains, enabling stable mRNA hybridization via A‐T pairing. Various metal ions were screened, and Mn 2 + was found to enhance mRNA endosomal escape and activate the STING pathway in DCs, promoting their maturation and antigen presentation. Controlled nanoparticle size (∼200 nm) and aptamer‐mediated DC targeting markedly enhanced lymphatic accumulation. In vivo evaluations revealed that COMPASS achieved potent prophylactic and therapeutic antitumor efficacy comparable to commercial LNPs (e.g., SM‐102), while exhibiting significantly enhanced safety profiles. Importantly, lyophilized COMPASS formulations retained their structural integrity and bioactivity for at least three months at room temperature. Overall, COMPASS represents a promising next‐generation nanoplatform with significant translational potential for safe and effective cancer immunotherapy.

Abstract Radiotherapy has demonstrated broad applications in treating solid tumors, but the hostile tumor microenvironment features significantly limit its clinical outcomes by impairing the priming of systemic antitumor immune responses. In this study, we developed a pH‐responsive nanomedicine by coating calcium carbonate nanoparticles with a quercetin‐zinc coordination polymer to potentiate radiotherapy through synergistic reprogramming of the immunosuppressive tumor microenvironment. Our results demonstrated that Zn 2+ induced pyroptosis in cancer cells further improves their immunogenicity, while quercetin upon being delivered to tumor sites significantly alleviates tumor hypoxia by sequentially decreasing extracellular collagen deposition and promoting tumor perfusion. The QZCaCO 3 ‐PEG, when administered intravenously, exhibited synergistic activity with localized X‐ray irradiation, triggering robust antitumor immunity and substantially inhibiting growth in both irradiated primary tumors and non‐targeted distant lesions. Additionally, QZCaCO 3 ‐PEG combined with radiotherapy elicited a durable immune memory response, effectively suppressing tumor recurrence in multiple murine rechallenge models. This study establishes a versatile strategy for designing multifunctional pH‐responsive nanomedicine as an immunogenic nano‐radiosensitizer to amplify radiotherapy via concurrent pyroptosis induction and tumor hypoxia alleviation.

Radiotherapy, while effective in tumor treatment, often induces upregulation of CD47 checkpoint expression on malignant cells, activating the CD47-SIRPα "don't eat me" signaling axis to inhibit macrophage-mediated phagocytosis, thereby promoting immune evasion and ultimately compromising therapeutic efficacy. Herein, a radiosensitizer-loaded biomimetic nanodecoy (p@MVs-Sirpα) is constructed by harnessing genetically engineered macrophage-derived vesicles to enhance tumor radioimmunotherapy. p@MVs-Sirpα displays the high surface expression of signal regulatory protein α (SIRPα), enabling it to selectively bind to CD47, a "don't eat me" signal overexpressed on tumor cells post radiotherapy, thereby competitively blocking the CD47/SIRPα immune checkpoint and promoting macrophage-mediated phagocytosis. Additionally, the nanodecoy is loaded with the radiosensitizing agent polyoxometalates (POMs), which further enhance the efficacy of radiotherapy by modulating the tumor immune microenvironment. This dual-function strategy not only facilitates the immune clearance of tumor cells but also potentiates radiotherapy-induced antitumor responses. p@MVs-Sirpα effectively inhibits the progression of established tumors in multiple murine models. Moreover, in tumor rechallenge experiments, robust and durable immune memory was observed, indicating long-term protection against tumor relapse. Collectively, this study provides a promising proof-of-concept for employing genetically engineered vesicle-based nanodecoy to disrupt radiation-induced immune escape and augment the therapeutic outcomes of radioimmunotherapy.

Neoadjuvant radiotherapy (NRT) is widely applied to reduce tumor burden and improve surgical outcomes. However, accumulating evidence indicates that radiation, at certain dose levels, paradoxically promotes the infiltration and polarization of tumor-associated macrophages (TAMs), especially the immunosuppressive M2-like subtype, thereby fostering an immunosuppressive tumor microenvironment (TME) and compromising long-term therapeutic efficacy. To overcome this limitation, we developed a biomineralized nanoghost platform (SBC@CaP) derived from senescent erythrocyte vesicles and coated with a pH-responsive calcium phosphate (CaP) shell. In the acidic TME, the CaP layer gradually dissolves, exposing the senescent erythrocyte membrane for selective recognition and uptake by TAMs, particularly those enriched after radiotherapy. Functioning as a universal TAM-targeting carrier, SBC@CaP can be modularly loaded with agents, such as disodium clodronate to induce apoptosis or ferrous ions to trigger ferroptosis in TAMs. In addition, released CaP buffers intratumoral acidity and enhance radiosensitization. This modular strategy enables precise TAMs clearance, TME remodeling, and immune activation. In multiple tumor models, SBC@CaP effectively reprograms the immune landscape and suppresses tumor progression, offering a versatile platform to mitigate the drawbacks of NRT and potentiate macrophage-targeted cancer therapy.

Tumor heterogeneity disrupts the consistent expression of target markers, leading to inefficient tumor targeting and contributing to drug resistance and relapse. Therefore, seeking a more universal target is crucial for enhancing drug enrichment in tumors. In this study, we propose a self-amplifying tumor-targeting strategy that leverages externalized phosphatidylserine (PtdSer) on apoptotic cells as a universal target. The system is composed of a Red Blood Cell-Liposome hybrid membrane camouflaged Mn-Ce6 nanocomplex, which is further modified with a PtdSer aptamer (MC@RL/Apt). MC@RL/Apt demonstrates prolonged circulation time and enhanced tumor accumulation, capable of inducing cancer cell apoptosis and PtdSer externalization under 660 nm light irradiation. The externalized PtdSer is then recognized by the PtdSer aptamer, which recruits additional MC@RL/Apt to the tumor site, facilitating a self-amplified tumor accumulation effect. In vitro studies show that MC@RL/Apt acted as an efferocytosis inhibitor, suppressing macrophage phagocytosis of apoptotic cells and promoting macrophage polarization toward the pro-inflammatory M1 phenotype. Compared to non-functionalized MC@RL, intravenous administration of MC@RL/Apt increases tumor accumulation by 1.46-fold under 660 nm light irradiation. As a result, treatment with MC@RL/Apt effectively suppressed tumor growth and induced robust antitumor immune responses. This work highlights a self-amplifying tumor-targeting strategy that leverages externalized PtdSer on apoptotic cells as a target to enhance tumor-specific drug delivery, while simultaneously inhibiting PtdSer-mediated macrophage engulfment, offering a promising approach for improving cancer therapy outcomes.

Tumor starvation therapy aims to deprive tumors of essential nutrients but is often hindered by incomplete vascular occlusion and tumor metabolic adaptation. In this study, a pH-responsive calcium carbonate (CaCO3) embedded porous poly (lactic-co-glycolic acid) (PLGA) microsphere is developed to co-deliver the small-molecule vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and thrombin, synergistically inducing cascaded intravascular coagulation and enhancing the efficacy of tumor-starvation therapy. The incorporation of CaCO3 nanoparticles not only increased the drug loading capacity but also endowed the microsphere with pH-responsiveness, enabling the sequential release of DMXAA under acidic conditions to disrupt blood vessels and induce procoagulant factors exposure, followed by the release of thrombin, which, in combination with the Ca2+ ions generated from the decomposition of CaCO3, further promoted blood clotting. In vascularized B16F10 murine melanoma models, these engineered microspheres demonstrate significant therapeutic potential through targeted induction of tumor-associated intravascular thrombosis, resulting in marked anti-tumor efficacy. Notably, in orthotopically implanted 4T1 mammary carcinoma models, the multifunctional particulates not only achieve primary tumor growth retardation but also effectively mitigate pulmonary metastatic dissemination. Thus, this work highlights a functional microsphere with sequential drug release capabilities, which can synergistically amplify tumor coagulation, leading to enhanced tumor-starvation therapy.

Rheumatoid arthritis (RA) is a globally prevalent autoimmune musculoskeletal disease that requires early-stage treatment. Initially, patients with RA exhibit elevated reactive oxygen species (ROS) levels and acidic conditions within the articular spaces. These two factors synergistically promote lipid peroxidation in M2 macrophages and lead to increased inflammation. Our work was then designed to engineer a multifunctional nanomedicine that targets the increased lipid peroxidation sensitivity of M2 macrophages. We successfully synthesized a calcium carbonate (CaCO3)-based nanomedicine via a biomineralization approach involving tannic acid (TA) and poly(ethylene glycol)-b-poly(glutamic acid). The TA@CaCO3 nanomedicine exhibited superior ability to neutralize acidity and scavenge ROS both in vitro and in vivo, effectively enhancing the lipid peroxidation resistance of M2 macrophages. Therefore, this nanomedicine significantly protected M2 macrophages and ameliorated the symptoms of arthritis, achieving therapeutic efficacy comparable to that of conventional methotrexate therapy. This study proposes a therapeutic strategy for regulating immunity by improving the pathological microenvironment within the joint cavity in rheumatoid arthritis patients.

The realization of tumor infarction therapy through the induction of tumor-localized thrombosis is an appealing cancer treatment strategy, but its therapeutic potency is severely hindered by posttreatment tumor relapse, which mainly results from incomplete intravascular thrombosis. Herein, a pH-responsive nanoreactor (coined as TLCaP2 NRs) is designed by enveloping thrombin and lipoxygenase within poly(ethylene glycol)-b-poly(glutamic acid) copolymeric micelles through the biomineralization growth of calcium phosphate. Thrombin is adopted to occupy tumor blood vessels through inducing intravascular blood clots, the polyunsaturated fatty acids of which are synergistically converted to cytotoxic lipid radicals by lipoxygenase and the released hemoglobin to induce ferroptotic cancer cell death. Upon tumor accumulation, TLCaP2 NRs could inhibit the growth of both CT26 and H22 tumors in mice through the enzymatic promotion of tumor-localized intravascular thrombosis and lipid peroxidation. Moreover, via the doping of Mn2+, which can activate the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the yielded TLCaMnP2 NRs showed potent tumor suppression efficacy through the enzymatic induction of cancer cell death and the elicitation of antitumor immunity. This work highlights an ingenious strategy to prepare immunogenic nanoreactors via a biomineralization process for the enzymatic induction of intravascular thrombosis and lipid peroxidation and the priming of antitumor immunity.

Photodynamic therapy (PDT) has been investigated for minimal invasive treatment of superficial tumors, but its clinical efficacy is constrained by its immediate light-dependent cytotoxicity, low immunogenicity, and other reasons. Building on the capacity of polyunsaturated fatty acids (PUFAs) to convert short-lived reactive oxygen species into longer-lived, highly cytotoxic lipid radicals, we develop a long-acting liposomal photosensitizer by co-encapsulating chlorin e6 (Ce6) and linoleic acid (LA) with commercial lipids. The resulting LA-Ce6@liposome converts short-lived singlet oxygens to persistent lipid radicals during light exposure, sustaining free LA peroxidation even post-irradiation. Mechanistic studies demonstrate that LA-Ce6@liposome-mediated PDT drives immunogenic ferroptosis and PANoptosis in cancer cells via amplified lipid peroxidation. In preclinical models, this strategy not only inhibits the growth of light-irradiated primary tumors but also activates systemic antitumor immunity, delaying progression of distal metastatic and rechallenged tumors, particularly when synergized with immune checkpoint blockade therapy. This study highlights a streamlined strategy to augment conventional PDT by integrating photosensitizers with PUFAs, offering prolonged tumoradical activity and immune activation.

Transcatheter arterial embolization (TAE) represents a preferred therapeutic modality with minimal invasiveness for unresectable intermediate and advanced hepatocellular carcinoma (HCC) patients. However, its therapeutic outcome is restricted by incomplete occlusion of the whole tumor vasculature and exacerbated tumor immunosuppression due to the lack of ideal embolic agents. Herein, procoagulant embolic microspheres with tunable sizes are prepared by loading thrombin into calcium carbonate (CaCO3) nanoparticle-embedded gelatin microspheres (Th-CaCO3@gelatin MSs) via a microfluidic process. In this system, the yielded Th-CaCO3@gelatin MSs are capable of occluding main tumor-feeding blood vessels, while the released thrombin and Ca2+ triggered by the acidic tumor microenvironment can synergistically promote the formation of intravascular blood clots to occlude tumor capillaries. Meanwhile, the embedded CaCO3 nanoparticles can work as proton sponges to neutralize tumor acidity and thus effectively reverse tumor immunosuppression. Resultantly, TAE treatment with Th-CaCO3@gelatin MSs exhibits the most effective tumor suppression efficacy on orthotopic N1S1 HCC rat xenografts without causing obvious toxic effects. Therefore, this study highlights that our biocompatible embolic microspheres are capable of potentiating conventional TAE treatment by promoting pH-responsive tumor vascular infarction and neutralizing the acidic tumor microenvironment, with great potential in clinical translation.

Nanomaterial-based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent "always ON" or single-parameter responsive signal output, substantial off-target effects, and high cost. Therefore, achieving in vivo easy-to-read tumor imaging and precise therapy in a multi-parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the "AND" Boolean logic algorithm to address these issues. iDNR-mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers "AND" hydrogen peroxide (H2 O2 ). Therefore, intelligent temperature-based in vivo easy-to-read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.