Crystalline organic nanomaterials with programmable photophysical functions hold great promise for precision medicine, however, achieving controlled crystallization and responsive activation remains challenging. Here we report a kinetically gated and self-limiting crystallization (KGSLC) strategy for constructing allosteric phototheranostic nanocrystals. Through rational molecular design, the TCF acceptor unit governs intrinsic size confinement via surface hydration, while the hydroxyl group directs hydrogen-bond-assisted π-π stacking to promote highly crystalline assemblies. The resulting HICyT nanocrystals (HICyT NCs) exhibit strong near-infrared absorption, dual-type reactive oxygen species generation, and catalase-like activity. A disulfide-bridged prodrug, (HICyT)2S, further encodes tumor microenvironment-triggered activation, converting into active HICyT NCs upon glutathione cleavage. The resulting nanocrystals enable deep-tissue penetration, bright albumin-activated NIR-I/II fluorescence, and potent in vivo tumor ablation under irradiation. This kinetically programmed crystallization integrates structural precision, spatiotemporal activation, and real-time imaging into a single organic platform, offering a promising route toward self-reporting phototheranostic materials.

Correction for ‘Cell membrane-coated nanomicrospheres mimicking stem cell functions enhance angiogenesis for dental pulp regeneration’ by Yao Chen et al. , Mater. Chem. Front. , 2025, 9 , 2384–2395, https://doi.org/10.1039/d5qm00098j.

Organic room temperature phosphorescence (RTP) materials, particularly those emitting in the near-infrared (NIR) region, hold great promise for bioimaging due to their deep-tissue penetration and minimal autofluorescence interference. However, achieving efficient NIR RTP with long lifetimes remains challenging due to inefficient triplet exciton utilization. Herein, we propose a dark triplet state activation strategy to achieve efficient NIR RTP by leveraging host–guest energy transfer. Using benzophenone derivatives (BP, OBP, MBP, PBP) as rigid host matrices with high intersystem crossing (ISC) efficiency and an NIR fluorophore (MPTCF) as the guest, we achieve efficient Dexter-type triplet-triplet energy transfer (TTET) that converts non-emissive host triplets into guest-centered NIR phosphorescence. Systematic optimization of the host–guest system has shown that PBP/MPTCF exhibits exceptional performance, including long phosphorescence centered at 705 nm, an ultralong phosphorescence lifetime (210.3 ms), and high ISC efficiency (44.4

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in hematologic malignancies, yet its durability is limited by insufficient expansion, persistence, and T-cell exhaustion. Basic leucine zipper ATF-like transcription factor (BATF) promotes CD8+ T-cell effector differentiation but can drive exhaustion under chronic stimulation. Here, we developed a transient, non-viral strategy to modulate BATF expression in therapeutic T cells using clinically approved lipid nanoparticles (LNPs). Among 3 Food and Drug Administration (FDA)-approved ionizable lipids, SM-102-based LNPs achieved the highest mRNA delivery efficiency in primary T cells. Transient BATF overexpression enhanced T-cell cytotoxicity in vitro without inducing exhaustion. In vivo, BATF mRNA transfection enhanced T-cell expansion, reduced exhaustion, and improved anti-tumor activity for both OT-1 TCR-T cells in melanoma and CD19 CAR-T cells in acute lymphoblastic leukemia. These findings establish a safe and reversible platform for transient transcription factor modulation to optimize T-cell differentiation and function, thereby enhancing the efficacy of adoptive T-cell therapies and supporting clinical translation.

Epithelial-mesenchymal transition (EMT) mediated metastasis remains the primary contributor to cancer-related mortalities worldwide, highlighting the critical need for therapeutic strategies that simultaneously eradicate primary tumors and suppress metastatic progression. However, conventional photodynamic therapy (PDT), particularly oxygen-dependent type-II photosensitizers, suffers from hypoxia-limited efficacy and may even induce EMT under suboptimal treatment conditions. Herein, we report enhanced type-I reactive oxygen species (ROS)-generating nanoparticles (NPs) based on the coassembly of two structurally similar small molecules (TQTT-NO and TQTT-NH), integrating light-controlled nitric oxide (NO) release to synergistically inhibit tumor growth and EMT. By leveraging precise molecular structure matching, the coassembled NPs (TQTT-NO/NH NPs) enable efficient intermolecular electron transfer, as revealed by the photocurrent results and Gibbs free energy calculations, thereby favoring type-I ROS generation under white-light irradiation while simultaneously triggering on-demand NO release. The developed TQTT-NO/NH NPs effectively suppress transforming growth factor-β (TGF-β)-induced EMT, inhibit cancer cell migration and invasion in vitro, and markedly reduce primary tumor growth and lung metastasis in a murine tumor model under light activation. Overall, this work establishes a generalizable molecular coassembly strategy for enhancing type-I PDT and EMT regulation, offering a promising paradigm for next-generation antimetastatic phototherapeutic platforms with translational potential.

Integrating bioorthogonal technology with organelle-targeted therapies can significantly enhance the precision of organelle anchoring. However, limited reports have mainly focused on mitochondria, lysosomes, or cell membranes, and studies on the endoplasmic reticulum (ER) are lacking. Moreover, improving tumor-specific selectivity in bioorthogonal therapies remains crucial for advancing future applications. Here, we introduce an ER-anchored bioorthogonal therapeutic system for specific tumor treatment. Based on the enzymatic reaction of phospholipase D1 (PLD1), trans-5-oxocene (oxoTCO) was first labeled onto the phospholipids that may accumulate on the ER through phospholipid transport. Subsequently, the tetrazine (Tz)-decorated aggregation-induced emission photosensitizer, Tz-TBR, was bound to oxoTCO via a bioorthogonal reaction. Therefore, the Tz-TBR was selectively anchored on the ER and transferred to the "turn-on" state. Upon light irradiation, the turned-on Tz-TBR induced tumor cells to undergo visualized ER stress by generating fluorescence and reactive oxygen species at the ER site, ultimately triggering immunogenic cell death. Notably, the tumor cell-specific high expression property of PLD1 endowed the system with high tumor selectivity. Overall, this work provides a novel tumor-specific ER-anchored bioorthogonal therapeutic strategy, which not only provides a promising method for tumor treatment but also broadens the application of bioorthogonal technology in tumor precision-targeted therapies.

Obesity is a chronic metabolic disorder associated with severe comorbidities and limited effective treatments, including lifestyle interventions, pharmacotherapies, and bariatric surgery. Photothermal therapy (PTT) offers a noninvasive alternative, yet few photothermal materials enable concurrent therapeutic and imaging functions. Herein, an injectable photothermal hydrogel with fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm) is reported, enabling in situ adipose tissue remodeling through mild, image-guided PTT. A pyrazine-based molecule, PPT-TPA8, was rationally engineered to integrate strong NIR absorption, bright NIR-II emission, and high photothermal stability. Incorporated into a PLGA-PEG-PLGA thermoresponsive matrix, it forms a hydrogel with controllable mild heating and sustained local retention under low-power irradiation. In vitro and in vivo studies show that the hydrogel under NIR irradiation induces adipocyte apoptosis and white-to-beige fat conversion, reducing fat accumulation and improving metabolism without systemic toxicity. Furthermore, NIR-II fluorescence enabled real-time, noninvasive tracking of hydrogel degradation and distribution. This biocompatible, image-guided, and minimally invasive platform provides a promising strategy for precise, localized antiobesity therapy.

Understanding the mechanisms limiting OX40 agonist antibody efficacy is critical for developing more effective combination immunotherapies. Tumor microenvironment (TME) analysis revealed that OX40-antibody-responsive mice harbored tumor-associated macrophages (TAMs) with elevated NOS2 expression and heightened pattern recognition receptor (PRR) activation and interferon gamma (IFN-γ) signaling. In addition, patients with more favorable treatment responses to OX40 antibody therapy exhibited increased NOS2 expression. Mechanistically, tumor-infiltrating T-cell-derived IFN-γ synergizes with endogenous ligands of PRR released during immunogenic cell death to drive NOS2+ TAMs reprogramming. Translating these insights into therapeutic strategy, a Combo approach composing of MPLA, IFN-γ, and OX40 agonist antibody is designed to actively polarize TAMs to express NOS2, which mediate tumor clearance through an NOS2-dependent cytotoxicity. Moreover, OX40-antibody-mediated regulatory T cell (Treg) depletion potentiated NOS2+ macrophage induction. This multimodal strategy offers a promising solution to overcome the limitations of OX40 antibody monotherapy and enhance outcomes of the OX40-targeted immunotherapies.

Molecular afterglow imaging is a biomedical modality with high sensitivity and specificity. However, due to the short half-lives of existing afterglow agents, longitudinal imaging often requires multiple on-site reinductions. Here we report a probe with month-long afterglow luminescence and the ability to target a downregulated liver tumour biomarker. This downregulated-biomarker-activatable afterglow probe (DROP) operates through a self-sustainable photoenergy cycling reaction, during which afterglow resonance energy transfer re-excites the afterglow initiator to regenerate singlet oxygen. This process initiates new afterglow resonance energy transfer cycles, extending the afterglow duration to over 40 days. The long afterglow of DROP enables in vivo imaging over 8 h with a single light preinduction, mimicking the imaging process of radioisotopes. Moreover, DROP quickly becomes inactive in healthy liver tissues due to cytochrome P450 enzyme activity, detecting and delineating tumours as small as 1 mm in diameter for complete surgical resection in both murine and rabbit models. Overall, we provide fundamental guidelines to develop radioisotope-mimetic afterglow luminescence probes and highlight the targeting of downregulated biomarkers as a promising approach in cancer theranostics.

Background OX40, a key co-stimulatory receptor that amplifies T cell-mediated anti-tumor immunity, is a promising immunotherapeutic target. Despite most reported OX40 agonists in clinical trials having high affinity, the relationship between affinity and agonistic activity remains complex, necessitating further clarification of affinity's impact on OX40-based immunotherapy efficacy and its underlying mechanisms.Methods We generated the different affinity OX40 agonist antibodies were generated by phage display. Antibody-receptor interactions were modeled using AI-based prediction and validated by hydrogen-deuterium exchange. We assessed the receptor clustering, T cell activation, and regulatory T cell (Treg) depletion effect of OX40 antibodies with different affinities by confocal microscopy and reporter cell assays. We further evaluated the anti-tumor efficacy in multiple murine tumor models. The effects of HFB301001 treatment on tumor-infiltrating T cells, safety in cynomolgus monkeys, and immune activation in clinical samples were investigated using single-cell RNA sequencing (scRNA-seq), flow cytometry, ELISpot, and immunofluorescence.Results We identified the low-affinity OX40 agonist antibody HFB301001 and generated variants with different affinities via phage display. Compared with its high-affinity mutant, HFB301001 induced stronger receptor clustering, enhanced T cell activation, and mediated more potent natural killer-mediated antibody-dependent cell-mediated cytotoxicity for Treg depletion than its high-affinity mutant in vitro. Consistently, HFB301001 outperformed the high-affinity mutant by boosting intratumoral T cell infiltration/activation and Treg clearance in vivo. Additionally, HFB301001 exhibited favorable safety in cynomolgus monkeys and effectively activated tumor-infiltrating T cells in a clinically relevant tumor slice culture system.Conclusions The reduced-affinity strategy represents a promising framework for the clinical development of OX40-targeted cancer immunotherapies. Currently, HFB301001 is concluding in a phase I clinical study involving patients with advanced solid tumors (NCT05229601).

Correction for ‘Highly effective DPA-SCP sonosensitizers for biofilm removal in infected root canals via sonodynamic therapy’ by Ziheng Zhang et al. , Mater. Chem. Front. , 2024, 8 , 3906–3918, https://doi.org/10.1039/d4qm00408f.

Lipid peroxidation (LPO) of tumor cell membranes is a pivotal executor of regulated cell death and a potent trigger for antitumor immunity. However, most LPO inducing strategies either depend on external irradiation and adequate oxygen supply or require broad disruption of the glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant axis. As a result, their performance is often compromised by limited tissue penetration, heterogeneous tumor microenvironments, insufficient tumor selectivity with potential off target toxicity, and adaptive anti-ferroptotic responses that blunt sustained LPO amplification. To address these challenges, we developed a precision enhanced singlet oxygen battery (SOB), termed GUIDE-SOB. By integrating tumor-specific recognition with enzyme guided, cell-associated self-assembly, GUIDE-SOB achieves spatiotemporally confined oxidative therapy. This design anchors the oxidative source on the plasma membrane for more than 12 h and concentrates oxidative flux onto lipid rich membrane domains that are highly susceptible to peroxidation. Sustained membrane oxidation reduces reliance on light penetration and alleviates hypoxia associated limitations, while overcoming cellular repair mechanisms to produce robust tumor suppression. Overall, this work establishes a membrane-targeted oxidative platform with prolonged activity, providing a promising strategy for treating deep-seated and therapy-resistant malignancies.

Purely organic room-temperature phosphorescence (RTP) is easily quenched by water and oxygen in aqueous systems, severely restricting its application in bioimaging. As two main strategies for achieving aqueous RTP, nanocrystallization and supramolecular self-assembly are not applicable to chromophores that lack crystal luminescence and matrix compatibility. Here, we provide an optional strategy, endogenous oxygen depletion-based emulsion polymerization nanospheres (NSs), for achieving aqueous RTP for the aforementioned chromophores. The aqueous RTP probe is constructed by encapsulating chromophores with high reactive oxygen species (ROS) generation capabilities into poly(methyl methacrylate) (PMMA) NSs prepared via emulsion polymerization. The dense and hydrophobic structure of PMMA NSs, combined with the high ROS generation efficiency of the incorporated chromophores, effectively suppresses phosphorescence quenching by water and oxygen, thereby enabling visible aqueous RTP in an air-exposed environment. In contrast, no RTP is observed in nanocrystalline and supramolecular systems with the same chromophores. The applications of these PMMA NSs in subcutaneous, tumor, and lymphatic tissue bioimaging are successfully demonstrated, with the signal-to-background ratio reaching as high as 556. This strategy is expected to provide a feasible route for developing aqueous-phase RTP nanoprobes and to advance the broader application of organic RTP probes in bioimaging.

Intravesical instillation of bacillus Calmette-Guérin (BCG) remains the standard-of-care immunotherapy for high-risk nonmuscle-invasive bladder cancer (NMIBC). However, its clinical efficacy is frequently compromised by rapid drug washout resulting from intermittent bladder voiding, whereas intensified dosing regimens are associated with severe adverse events, including tuberculous cystitis and hematuria. Herein, we report an enzyme-responsive peptide, D-Nap-GFFYp, that undergoes alkaline phosphatase (ALP)-triggered self-assembly into a hydrogel selectively at the NMIBC tumor site. Using tumor-bearing mouse models, we demonstrate that simultaneous intravesical administration of D-Nap-GFFYp and BCG induces in situ gelation, forming a BCG-encapsulated hydrogel depot that enables sustained local release. This strategy markedly prolongs BCG retention within the bladder, thereby eliciting continuous immune stimulation characterized by enhanced M1 macrophage polarization and suppression of the pro-tumorigenic M2 phenotype. Importantly, localized hydrogel formation minimizes off-target exposure to high BCG concentrations, substantially reducing treatment-associated toxicity. Collectively, D-Nap-GFFYp functions as an effective and safe tumor-localized immune adjuvant, establishing a versatile platform for long-term BCG delivery. This work presents a rational and clinically translatable approach to improve the efficacy and biosafety of bladder cancer immunotherapy.

Photodynamic therapy (PDT) has been shown to improve survival and quality of life in patients with unresectable extrahepatic cholangiocarcinoma. However, its therapeutic efficacy is frequently limited by the survival of residual tumor cells that can re-enter the proliferative cycle. Our previous studies showed that residual cholangiocarcinoma cells can re-enter the proliferative cycle following PDT accompanied by hypoxia-induced activation of the HIF-1α survival pathway and intracellular antioxidant programs. To address this residual viability, we developed a glutathione-responsive targeted nanosystem (TSH NPs), in which the aggregation-induced emission (AIE) photosensitizer TPA-Ph-RDN is conjugated to the chemotherapeutic agent hydroxycamptothecin (HCPT) via a disulfide linkage. This design enables HCPT to exert direct cytotoxic effects while simultaneously suppressing the HIF-1α-mediated hypoxic adaptation pathway, thereby reducing residual tumor viability and enhancing PDT efficacy. This strategy achieves a dual-mechanism, two-pronged therapeutic effect. Both in vitro and in vivo studies demonstrated that TSH NPs elicited markedly synergistic antitumor activity, highlighting their potential as a promising therapeutic approach for improving clinical outcomes in patients with eCCA.

Tumor glycolysis supports malignant progression and promotes an immunosuppressive microenvironment, but glycolysis blockade alone often gives limited therapeutic benefit because tumor cells can adapt metabolically and metabolic inhibition does not necessarily elicit antitumor immunity. Here, we report a metabolically reprogrammable nanoplatform, TCP@PRL3 nanoparticles (TCP@PRL3 NPs), integrating an aggregation induced emission photosensitizer with a phosphatase of regenerating liver 3 (PRL3) inhibitor for combined photodynamic and immunometabolic therapy. Upon irradiation, TCP@PRL3 NPs generated reactive oxygen species (ROS) to induce immunogenic cell death (ICD), while PRL3 inhibition suppressed glycolysis, reduced lactate production, and alleviated tumor acidification. In multiple myeloma (MM) cells, TCP@PRL3 NPs decreased adenosine triphosphate (ATP) and lactate levels, downregulated pyruvate kinase M2 (PKM2), and inhibited extracellular acidification and oxygen consumption. These metabolic changes promoted dendritic cell maturation, reduced senescent T cell populations, expanded activated CD27+CD28+ T cells, and increased secretion of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 2 (IL-2). In a humanized MM model, TCP@PRL3 NPs markedly inhibited tumor growth, and combination with daratumumab further improved efficacy without evident systemic toxicity. The platform also suppressed CT26 and 4T1 tumors by enhancing dendritic cell activation, CD8+ T cell responses, and intratumoral metabolic remodeling. These findings identify TCP@PRL3 NPs as a promising immunometabolic nanoplatform for metabolically active tumors.

The cancer-immunity cycle (CIC) provides a conceptual framework for eliciting effective anti-tumor immune responses by targeting key events in systemic immunity. However, the successful completion of the CIC often requires the coordinated action of multiple therapeutic modalities, necessitating their integration into a unified system to overcome the limitations of conventional combination therapies. Here, we present a multimodal and programmable platform that integrates diverse therapeutic biomolecules into single agents, enabling the construction of versatile nanomedicines and bispecific antibodies through dual-targeted nano-adaptor (TNA) nanotechnology to potentiate the CIC. Specifically, TNA nanomedicines target five critical steps within the CIC, including antigen release, dendritic cell (DC) maturation, T-cell activation, mitigation of T-cell exhaustion, and tumor cell killing. Meanwhile, TNA bispecific antibodies enhance DC-T cell interactions to strengthen adaptive immunity and reinforce NK-tumor cell interactions to promote cytotoxicity. We demonstrate that TNAs elicit robust anti-tumor immunity, eradicating established tumors and suppressing metastatic dissemination. Owing to their modular and programmable architecture, TNAs hold broad potential for applications in immunotherapy and beyond.

It has been highly challenging to reliably detect various cancers at an early stage when tumors are just millimeters in size. To address this, we developed a tumor microenvironment (TME)-responsive nanoprobe, PR-KAd@CD-AuNC, enabling cross-validated cancer detection through in vivo second near-infrared (NIR-II) fluorescence imaging and in vitro colorimetric urinalysis. The nanoprobe consists of three integrated components: a renal-clearable signal-output segment (cyclodextrin-functionalized gold nanocluster, CD-AuNC), a tumor-targeting and size-controlling component (PR), and a matrix metalloproteinase-2 (MMP2)-cleavable linker (KAd). PR, composed of 8-arm poly(ethylene glycol) for prolonged circulation and c(RGDfK) peptides for αvβ3 integrin targeting, directed selective tumor accumulation after intravenous injection of PR-KAd@CD-AuNC. The intrinsic emission of CD-AuNC above 1100 nm enabled high-resolution, real-time NIR-II fluorescence imaging with attenuated photon scattering, allowing precise tumor delineation. Within the TME, specifically overexpressed MMP2 cleaved the KAd linker, releasing ∼2 nm CD-AuNC fragments from the ∼10 nm parent nanoprobe. Being smaller than the ∼5.5 nm renal filtration threshold, these fragments were renally excreted. Concurrently, the peroxidase-like activity of CD-AuNC catalyzed tetramethylbenzidine oxidation to produce a visible blue signal, providing a simple and low-cost urinalysis method suitable for broad cancer screening applications. This dual-modality strategy effectively distinguished cancers from inflammation and other diseases, detecting small tumors for multiple cancer types with a sensitivity surpassing that of computed tomography (CT) imaging, which makes it a promising early detection approach. Furthermore, it was also employed to dynamically assess cancer therapeutic efficacy (i.e., immunotherapy, chemotherapy, and surgical resection), suggesting clinical value for guiding treatment decisions.

Uncovering novel targets that synergize with immune checkpoint blockade (ICB) is an urgent clinical priority. While cancer cell-intrinsic CD28 facilitates immune escape by functioning as a non-classical RNA-binding protein to stabilize CD274 (PD-L1) mRNA, inhibiting this pathway in cancer cells without impairing essential T cell CD28 costimulation remains a major structural challenge. Here, we report the development of a 16:0 LPC-modified SM102-based lipid nanoparticle (LPC-LNP) that exploits altered tumor lipid metabolism for highly selective cancer cell transfection. By leveraging elevated lysophosphatidylcholine acyltransferase (LPCAT) uptake mechanisms inherent to malignant cells, LPC-LNPs efficiently deliver Cd28 small interfering RNA directly to tumor cells while strictly avoiding T cell sequestration. In vivo administration of LPC-LNP-Cd28 successfully knocked down 80% of cancer cell CD28, substantially reduced PD-L1 expression, and circumvented the off-target immunosuppression observed with commercial lipid formulations. Consequently, targeted Cd28 silencing reshapes the immunosuppressive tumor microenvironment, augmenting twofold CD8+ T cell infiltration and dendritic cell activation to extend survival in murine breast and lung cancer models to 1.3-1.5 folds. Furthermore, the combined use of LPC-LNP-Cd28 effectively eradicates resistance to anti-PD-1 therapy. This study provides a highly translatable, cancer-specific nanomedicine platform, confirming that selectively antagonizing tumor-intrinsic CD28 holds profound promise for advanced cancer immunotherapy.