Although low-dose radiotherapy (LDRT) exhibits high potential for radiotherapy, it meets a cascade of limitations for effectively eradicating refractory tumors due to low cell-killing effects, insufficient reactive oxygen species (ROS) production and acquired radio-resistance. Here, we engineered a new type of self-oxygenating nanoreactor (HCCP) to relieve hypoxia and effectively eradicate radio-resistant triple-negative breast cancer (TNBC) by combining low-dose X-ray-induced photodynamic therapy (LX-PDT), cuproptosis and chemodynamic therapy (CDT), which was further discovered to trigger the stimulator of interferon genes (STING) pathway for immunotherapy. HCCP was engineered by self-assembling hyaluronic acid-shielded ultrasmall calcium peroxide nanodots onto Cu-porphyrin coordinated core nanoparticles. HCCP can target breast cancer cells to supply O2 and H2O2 to relieve hypoxia, generate ROS, and induce cuproptosis and apoptosis by Cu, CDT and LX-PDT. By i.v. injection, HCCP exhibited high tumor accumulation and alleviated tumor hypoxia, leading to effective eradication of conventional, large and radio-resistant TNBC upon low-dose X-ray irradiation with promoted survival rates. Additionally, HCCP was further found to activate STING and elicit robust antitumor immunity for potently inhibiting distant and metastatic TNBC. Collectively, this study presents an effective nanoreactor-based strategy to overcome the limitations of LDRT for potently treating refractory TNBC malignancies, and highlights its potential for further translational development.

Metal-organic frameworks (MOFs) are a unique class of porous materials constructed from metal-containing nodes, known as secondary building units (SBUs) and organic ligands. Their highly tunable structures enable the encapsulation of a broad range of therapeutic agents, spanning small-molecule chemotherapeutics to biomacromolecules such as proteins, DNA, and RNA. By rational selection of metal ions and organic linkers, diverse functionalities, including molecular imaging and phototherapeutic capabilities, can be included into MOFs, rendering them promising nanoscale platforms of nanomedicines. In this review, we summarize recent advances of MOFs for drug delivery, cancer imaging and theranostics. We discuss the progress in regulating the morphology and functions of MOFs through diverse synthetic strategies and surface modification approaches. We further systematically analyzed and discussed MOFs in the applications of drug delivery, molecular imaging, and cancer theranostics, with recent strategies. Finally, key limitations associated with the clinical translation of MOFs are discussed, along with the corresponding bottlenecks, future challenges, and emerging opportunities.

Chronic inflammation in intermediate/advanced tumors drives burdensome protumor immune cell communication, thereby weakening immunotherapy. Conventional anti-inflammatory therapies focus on alleviating chronic inflammation whereas ignore dysfunction and scarcity of myeloid and T cells, which hinder their intercellular communication restoration. To address the dilemma, an inflammatory condition-triggered protumor inflammation-immunosurveillance shift hydrogel (TRANS) is developed to initiate adaptive immune responses mediated by intercellular communication. Triggered by inflammatory conditions, TRANS releases celecoxib (CXB) to inhibit the COX-2/PGE2 pathway, thereby reprogramming tumor-associated macrophages and mitigating protumor inflammation. Furthermore, TRANS incorporates FMS-like tyrosine kinase 3 ligands (Flt-3L) and 4-1BB agonists (α-CD137) to respectively recruit type 1 conventional DC (cDC1) and revitalize tumor-infiltrating T cells, to rejuvenate immunosurveillance. TRANS inhibits 87.50% and 88.74% of primary and secondary colorectal tumors, generates antitumor immune memory to resist tumor rechallenge, and significantly reduces lung and liver metastases. Rechallenge model shows TRANS leads to antitumor immune memory formation. Single-cell RNA sequencing is preform to elucidate the mechanism of TRANS, which exhibits that TRANS exerts antitumor effects by optimizing the crosstalk between myeloid cells and T cells via CXCL9/10-CXCR3/DPP4. TRANS further gains better control of colorectal cancer when combined with immune checkpoints inhibitors. This study offers a novel perspective on immunotherapy by rebalancing inflammation-immunity dynamics.

Vaccination is an important approach for cancer immunotherapy, but is limited by the inefficient delivery of immunogenic antigens to dendritic cells (DCs) to stimulate tumor-specific immune responses. Herein, we engineered glucosylated lipid nanoparticles (GluLNPs) to deliver tumor antigens and form personalized vaccines in situ, efficiently targeting DCs to stimulate robust antitumor immunity for the immunotherapy of low-immunogenic breast cancer. Through intratumoral injection, GluLNPs can efficiently capture and deliver tumor antigens, including neoantigens released from eradicated primary triple-negative breast tumors after mild phototherapy with photosensitizer-loaded nanoparticles (i.e., ICGNPs), to DCs, thereby triggering DC maturation and robust antitumor immune responses. Moreover, GluLNPs can effectively elicit strong systemic antitumor immunity against distant and metastatic triple-negative breast tumors when combined with immune checkpoint blockade. This study presents a practical strategy for developing effective DC-targeting personalized nanovaccines and in situ vaccination for precise and effective tumor immunotherapy.

Hybridization chain reaction (HCR), which typically consists of two hairpins for signal amplification, has emerged as a versatile tool in bioanalytical applications. Here, a novel HCR nanowire based on a single DNA hairpin structure is reported. The hairpin stem is rationally engineered with a palindromic sequence, which enables a self-hybridization chain reaction (SHCR) upon the introduction of the initiator DNA strand. Compared to the conventional two hairpin-based HCR nanowire, the single DNA hairpin-based SHCR nanowire achieves nearly a two-fold improvement in the signal-to-noise ratio and exhibits better selectivity for single-base mismatch. By integrating the initiator DNA strand with adenosine triphosphate (ATP) aptamer, the single DNA hairpin-based nanowire has been applied for sensitive ATP detection, capable of monitoring ATP both in living cells and that released from dead cancer cells post-radiotherapy. The SHCR nanowire we proposed here has significantly simplified the sequence design of HCR and holds promise as a potential alternative to the conventional HCR nanowire.

The low immunogenicity and immune escape are bottlenecks for effective tumor immunotherapy. Here, we synthesized multifunctional polymers comprising a photosensitizer and cationic and thiol derivates and engineered a galactose-installed stimulator of interferon genes (STING) agonist and programmed death ligand 1 (PD-L1) small interfering RNA (siPDL1)-encapsulated nanocarriers (cGAMP-siPDL1@GalNPs) for synergistic immunotherapy of low immunogenic tumors through stimulating robust immune responses. cGAMP-siPDL1@GalNPs efficiently delivered the drugs into cancer cells by targeting the galactose receptors to trigger photo-/redox-/pH-activated drug release. cGAMP-siPDL1@GalNPs stimulated robust antitumor immunity via STING activation and immunogenic cell death (ICD) and inhibited immune escape via knockdown of PD-L1 expression in tumors, which synergistically regulated the immune-suppressive tumor microenvironment. Upon laser irradiation, the nanocarriers efficiently eradicated primary melanoma and orthotopic triple-negative breast tumors and induced ICD effects, which synergically inhibited the distant tumor and spontaneous lung metastasis with improved survival rates. This study presents a strategy for developing nanocarriers to activate antitumor immunity and regulate immune invasion for effective immunotherapy.

A major obstacle in knocking down oncogenes for tumor therapy is the efficient delivery of siRNA into the cytosolic spaces of cancer cells. Here, we genetically bioengineer biomimetic nanovesicles with tumor-recognition and enzyme-controlled membrane fusion functions for efficiently delivering small interfering RNA into cancer cells towards gene silencing tumor therapy. The siRNA@eS-BNVs are formulated by encapsulating siRNA inside the core and coating with genetically engineered HEK293TACE2- cell membranes encoded with functional S protein, which can recognize cancer cells and initiate membrane fusion when triggered by the enzyme. The siRNA@eS-BNVs demonstrate better efficacy for cytosolic siRNA delivery and RNA interference than conventional formulations. By intravenous injection, siRNA@eS-BNVs are highly accumulated in tumors and potently inhibited tumor and lung metastasis by simultaneously silencing the epidermal growth factor receptor gene in vivo. The cancer cell-targeting and enzyme-activatable nanovesicles provide a valuable strategy for effective and precise drug delivery.

Radiotherapy (RT) inhibits local tumors by stimulating reactive oxygen species (ROS) generation, and sometimes suppresses distant tumors known as the abscopal effect. However, the abscopal effect is rarely observed in clinic, due to insufficient tumor-associate antigens (TAAs) and weak immune stimulation. Here, a radiation-activated and self-cascade nano-immunostimulator (RAIDER) is fabricated to trigger a potent abscopal effect against distant tumors by unleashing cascade-amplified ROS generation and boosting antigen presentation. After accumulation in tumors, RAIDER undergoes HAase-triggered deshielding and charge-reversal, and GE11 enriched liposomal core and CpG are both released. Under following RT, protoporphyrin IX-induced Cherenkov radiation-photodynamic therapy (CR-PDT) elicits ROS generation, leading to disintegration of RAIDER and catalase (CAT) burst release. Meanwhile, by the combination of RT, CR-PDT, and CAT-induced O2 supply, self-cascade ROS generation is achieved to enhance lysis of tumor cells and release of massive TAAs. Subsequently, the co-stimulation of TAAs and the released CpG activates dendritic cell maturation to boost antigen presentation, resulting in a strong systemic immune response. Combined with RT, RAIDER exhibits a potent abscopal effect, with an average distant tumor growth inhibition of approximate to 70.3%. Overall, the strategy amplifies antitumor effect of RT from local to systemic, holding a potential against local and distant tumors.

X-ray-induced photodynamic therapy (X-PDT) shows significant promise in tumor treatments due to its unlimited tissue penetration but requires delivering sensitizers to tumors. Here, we engineered photosensitizer verteporfin (VP) and T-lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitor OTS964-encapsulated polymeric nanocarriers (VP/OTS964@NPs) for effective tumor X-PDT, molecule-targeted therapy and inducing robust antitumor immunity for synergistic immunotherapy of low immunogenic breast tumors and their lung metastases when combined with PD-L1 blockade. The VP/OTS964@NPs are monodisperse and can be disassembled to release drugs in response to high reactive oxygen species (ROS) levels in the tumor microenvironment or generated during X-PDT. It can efficiently deliver drugs into the TOPK-high expression breast cancer cells, generate ROS and induce ICD effects. By i.v. injection, VP/OTS964@NPs efficiently accumulated in the breast tumors and effectively eradicated tumors upon X-PDT. Additionally, the VP/OTS964@NPs activated the systemic antitumor immune responses, significantly inhibited the distant breast tumors and the lung metastasis of breast tumors, and enhanced the survival rates in combination with PD-L1 blockade. This study presented a strategy for engineering nanocarriers for synergistic molecular therapy, tumor XDT and immunotherapy. Statement of Significance X-PDT is a promising therapeutic modality for cancer treatment. However, its clinical application is hindered by the limited availability of suitable sensitizers and their insufficient tumor-targeting capability. This work aims to construct ROS-sensitive nanocarriers co-loaded with the photosensitizer verteporfin and the TOPK inhibitor OTS964 to achieve synergistic X-PDT for triple-negative breast cancer. By further activating antitumor immune responses, this strategy is designed to suppress the distant and metastatic breast tumors. Overall, this work provides both a nanodrug platform and a therapeutic strategy for the treatment of poorly immunogenic solid tumors.

The CRISPR/Cas9 system is revolutionizing genetic medicine by enabling programmable genome editing with unparalleled preci-sion and versatility1.Its therapeutic potential in oncology is particularly compelling,as targeted disruption of oncogenes or driver mutations could directly eliminate malignant cells2.

The design of ultrasound (US)-responsive nanocarriers (URNs) guided by their physicochemical characteristics represents a pivotal strategy for advancing cancer therapy. By exploiting the intrinsic physicochemical properties of diverse nanocarriers, including liposomes, polymers, nanobubbles (NBs)/nanodroplets (NDs), inorganic composites, and metal-organic frameworks (MOFs), URNs achieve precise spatiotemporal control over drug delivery, enhanced tumor penetration, and synergistic therapeutic outcomes under US stimulation. Leveraging US-induced mechanical and thermal effects, URNs exhibit expanding multimodal capabilities, encompassing gene delivery, chemo-sonodynamic therapy, immunomodulation, and gas-mediated reprogramming of the tumor microenvironment (TME). Despite significant preclinical progress, the clinical translation of URNs requires addressing key challenges: (1) inconsistent pharmacokinetics and long-term biosafety profiles; (2) insufficient targeting efficiency due to tumor heterogeneity; (3) a lack of standardized US parameter protocols to balance cavitation and thermal effects; and (4) challenges in scalable manufacturing and quality control. This review systematically evaluates the structure-property-function correlations in URN design, analyzes the physicochemical determinants of acoustic responsiveness alongside current limitations, and proposes a roadmap that integrates computational modeling, stimuli-responsive materials, and artificial intelligence (AI)-assisted parameter optimization to advance next-generation URNs, ultimately outlining future directions for personalized oncology and clinical translation.

Immune checkpoint blockade (ICB) has potential in alleviating cytotoxic T lymphocyte (CTL) exhaustion. However, resistance that impaired major histocompatibility complex class I (MHC-I) expression on tumors can be developed in many patients after ICB treatment, resulting in insufficient antigen presentation to CTLs. Herein, we rationally design a versatile and powerful immunomodulated hierarchical nanoCRISPR converter (SWITCH) targeting PD-L1 and PCSK9 loci to convert the immune-resistance state of tumors with high PD-L1 and low MHC-I expression for augmenting the susceptibility and visibility of tumors to the immune system. SWITCH possesses enhanced blood circulation and tumor-targeting capacity through PEGylation, acid-triggered pH low insertion peptides (pHLIPs), and interaction of hyaluronan with CD44 receptors. With the assistance of hyaluronidase and preternatural oxidative stress within tumor cells, SWITCH undergoes enzyme-responsive disassembly, charge reversal, rapid lysosomal escape, and efficient disruption of PD-L1 and PCSK9 orderly. This dual-action mechanism simultaneously blocks PD-1/PD-L1 immunosuppression while restoring MHC-I-mediated antigen presentation, resulting in enhanced the susceptibility and visibility of tumors to the immune system. Our results demonstrate SWITCH's remarkable efficacy in suppressing primary, contralateral, and recurrent tumor growth. Taken together, our study provides an encouraging strategy for relieving tumor immune resistance and further potentiating the efficacy of ICB.

High stability of selenium nanoparticles (SeNPs) is crucial for preserving their biochemical properties. Currently, surface modification is one of the most effective routes to improve the stability of nanoparticles. Herein, we synthesized SeNPs through a mild reduction reaction at room temperature. Subsequently, the SeNPs were simultaneously coated with polyvinylpyrrolidone (PVP) and glucose to improve stability, the obtained composite was abbreviated as PG-SeNPs. Results demonstrated that PG-SeNPs displayed excellent stability without any coagulation even when stored for as long as 2 months. The hydrodynamic particle size remained almost uniform. After that, doxorubicin (DOX) was loaded onto the surface of PG-SeNPs via electrostatic interaction, resulting in PG-SeNPs@DOX, with a loading efficiency of 4.53 +/- 0.3 %. In addition, the biocompatibility of PG-SeNPs was conducted and proven to be excellent. Consequences obtained in both in the in vitro and in vivo studies revealed that the PG-SeNPs@DOX could effectively kill the tumor cells and remarkably inhibit the growth of the transplanted tumor. We proposed that the antitumor efficacy obtained above was primarily dominated by the synergistic effect of both the reactive oxygen species induced by SeNPs and the released DOX. In summary, this study presents a straightforward and plausible method for producing highly stable SeNPs, and further confirms the antitumor effectiveness of PG-SeNPs@DOX.

Castration-resistant prostate cancer (CRPC) is an intractable disease, but approaches for eradicating primary tumors and inhibiting metastasis are limited. Considering that lipid metabolism plays key roles in ferroptosis and tumor progression and treatment resistance, here we developed a biomimetic nanovesicle (FiFe@RBM) encapsulating fatty acid synthetase inhibitors and iron oxide nanoparticles for synergistic therapy of CRPC and inhibiting the metastasis. FiFe@RBM with superior magnetic properties efficiently delivered drugs into the CRPC cancer cells, where it can release Fe ions to efficiently induce reactive oxygen species and mitochondrial dysfunction and inhibit the AKT-mTOR pathway, which synergistically causes apoptosis and enhances ferroptosis by rewired lipid metabolism through increasing polyunsaturated fatty acids (PUFAs), PUFA-enriched phosphatidylcholine (PUFA-PC), PUFA-enriched phosphatidylethanolamine (PUFA-PE), etc. By intravenous injection, the high accumulation of FiFe@RBM in PC-3 tumors enabled precision T1/T2-weighted magnetic resonance imaging-guided effective eradication of human CRPC PC-3 tumors by synergistic magnetic hyperthermia therapy (MHT) and ferroptosis, which further inhibited liver metastasis by the activated and recruited high rates of natural killer cells in the nude mice model. This work presents an effective nanovesicle strategy for reprogramming lipid metabolism to enhance ferroptosis in synergy with MHT for effectively treating refractory cancers.

Engineering nanovaccines capable of targeting dendritic cells (DCs) is desperately required to maximize antigen cross-presentation to effector immune cells, elicit strong immune responses, and avoid adverse reactions. Here, we showed that glucose transporter 1 (Glut-1) on DCs is a reliable target for delivering antigens to DCs, and thus, a versatile antigen delivery strategy using glucosylated nanovaccines was developed for DC-targeted antigen delivery and tumor immunotherapy. The developed glucosylated ovalbumin-loaded nanovaccines highly accumulated in lymph nodes and efficiently engaged with Glut-1 on DCs to accelerate intracellular antigen delivery and promote DC maturation and antigen presentation, which elicited potent antitumor immunity to prevent and inhibit ovalbumin-expressing melanoma. Moreover, immunotherapeutic experiments in DC- and macrophage-depleted animal models confirmed that the glucosylated nanovaccines functioned mainly through DCs. In addition, the neoantigen-delivering glucosylated nanovaccines were further engineered to elicit tumor-specific immune responses against MC38 tumors. This study offers a DC-targeted antigen delivery strategy for cancer immunotherapy.

Polymer-drug conjugates and polymer-protein conjugates have been pivotal in the realm of drug delivery systems for over half a century. These polymeric drugs are characterized by the conjugation of therapeutic molecules or functional moieties to polymers, enabling a range of benefits including extended circulation times, targeted delivery, controlled release, and decreased immunogenicity. This review delves into recent advancements and challenges in the clinical translations and preclinical studies of polymer-drug conjugates and polymer-protein conjugates. The design principles and functionalization strategies crucial for the development of these polymeric drugs were explored followed by the review of structural properties and characteristics of various polymer carriers. This review also identifies significant obstacles in the clinical translation of polymer-drug conjugates and provides insights into the directions for their future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Cancer immunotherapy is generally limited by the low immunogenicity of tumor microenvironments (TME). Thus, regulating immune responses in low immunogenic solid tumors is critical for improving immunotherapeutic outcomes. Here, the tumor-targeting and activatable biomimetic nanococktails have been engineered to synergistically and systemically activate a cascade of immune responses and downregulate immunosuppressive T cells for spatiotemporal immunotherapy of low immunogenic solid tumors. The nanococktails had core-shell structures, where the photosensitizers, STING agonists and indoleamine 2,3-dioxygen-ase 1 (IDO1) inhibitors were encapsulated within the core, which can disassociate when responding to the low pH in tumors to disrupt the particle shells and cellular membranes for precision drug delivery and release. The ligands anchored on the shell of nanococktails could efficiently target the receptors that were identified to be highly expressed in the breast cancer cells, facilitating efficient intracellular drug delivery and synergistically inducing anticancer immunity and mitochondrial damage. By intravenous (i.v.) injection, the nanococktails demonstrated high accumulation in triple-negative breast cancer (TNBC), endowing precision diagnosis and effective elimination of primary TNBC tumors. The synergistic effects of STING activation and metalloimmunotherapy induced by nanococktails can amplify systemic immune responses and downregulate immunosuppressive regulatory T cells (Tregs) in primary tumors, lymph nodes and distant tumors, which spatiotemporally inhibited distant tumors and lung metastasis of TNBC with promoted survival rates. This study presents a promising strategy for leveraging nanococktails to regulate immune responses for effective immunotherapy.