Advanced Materials

Designed Concave Octahedron Heterostructures Decode Distinct Metabolic Patterns of Epithelial Ovarian Tumors

AbstractEpithelial ovarian cancer (EOC) is a polyfactorial process associated with alterations in metabolic pathways. A high‐performance screening tool for EOC is in high demand to improve prognostic outcome but is still missing. Here, a concave octahedron Mn2O3/(Co,Mn)(Co,Mn)2O4 (MO/CMO) composite with a heterojunction, rough surface, hollow interior, and sharp corners is developed to record metabolic patterns of ovarian tumors by laser desorption/ionization mass spectrometry (LDI‐MS). The MO/CMO composites with multiple physical effects induce enhanced light absorption, preferred charge transfer, increased photothermal conversion, and selective trapping of small molecules. The MO/CMO shows ≈2–5‐fold signal enhancement compared to mono‐ or dual‐enhancement counterparts, and ≈10–48‐fold compared to the commercialized products. Subsequently, serum metabolic fingerprints of ovarian tumors are revealed by MO/CMO‐assisted LDI‐MS, achieving high reproducibility of direct serum detection without treatment. Furthermore, machine learning of the metabolic fingerprints distinguishes malignant ovarian tumors from benign controls with the area under the curve value of 0.987. Finally, seven metabolites associated with the progression of ovarian tumors are screened as potential biomarkers. The approach guides the future depiction of the state‐of‐the‐art matrix for intensive MS detection and accelerates the growth of nanomaterials‐based platforms toward precision diagnosis scenarios.

Mass‐Manufactured Gradient Plasmonic Metasurfaces for Enhanced Mid‐IR Spectrochemical Analysis of Complex Biofluids

Abstract Mid‐infrared (Mid‐IR) spectroscopy offers powerful label‐free molecular analysis capabilities but faces significant challenges when analyzing complex biological samples. Here, a transformative surface‐enhanced infrared absorption spectroscopy (SEIRAS) platform is presented that overcomes fundamental limitations through key innovations. First, high‐throughput wafer‐scale fabrication of mid‐IR plasmonic micro‐hole‐array (MHA) metasurfaces is demonstrated on free‐standing silicon nitride (Si 3 N 4 ) membranes, yielding ≈400 sensor chips per 6‐inch wafer. Second, the gradient MHA metasurface design supports spectrally cascaded plasmonic modes, generating over 400 sharp resonance peaks across the 1200–2000 cm −1 fingerprint region. This approach enables comprehensive molecular fingerprinting using simple imaging optics in transmission mode. Third, the SEIRAS platform is validated using a model polymer system and clinical peritoneal fluid samples from ovarian cancer patients, demonstrating its capability to resolve complex molecular signatures in real biological specimens. The platform's dense spectral coverage ensures optimal on‐resonance enhancement across the broad fingerprint region, revealing previously obscured vibrational bands that conventional IR spectroscopy cannot distinguish. By combining high‐throughput fabrication with simplified optical readout and the capability to analyze complex biological samples, this work establishes a foundation for translating SEIRAS technology into practical biomedical applications, promising a real‐world impact.

Molecular Imaging of Ovarian Follicles and Tumors With Near‐Infrared II Bioconjugates

AbstractFollicular tracking is typically conducted using ultrasound technology, but its effectiveness is constrained by limited resolution. High‐resolution imaging of deep tissues can be accomplished using luminescence imaging in the near‐infrared II window (NIR‐II, 1000–1700 nm); however, the contrast agents that are used lack specificity. Here, it is reported that the FDA‐approved indocyanine green (ICG)‐conjugated recombinant human chorionic gonadotropin (hCG) protein can target early follicles with long‐term effectiveness. A novel high‐resolution NIR‐II imaging approach is developed for monitoring follicular development as well as ovulation using multi‐color imaging of ovarian vessels with a combination of non‐overlapping downconversion nanoparticles (DCNPs). The results showed that the ability to monitor early follicles of around 50 µm in diameter exceeded the spatial and temporal resolution of ultrasound or MRI without the reproductive damage associated with computed tomography radiation, and this enabled the clinical identification of the follicular reserve in patients with infertility diseases such as polycystic ovary syndrome (PCOS). In addition, NIR‐II imaging clearly targeted ovarian tumors and showed micro‐metastatic lesions, thus providing a new tool for monitoring tumors in vivo and guiding surgical resection.

Surface Plasmon‐Enhanced Short‐Wave Infrared Fluorescence for Detecting Sub‐Millimeter‐Sized Tumors

AbstractShort‐wave infrared (SWIR, 900–1700 nm) enables in vivo imaging with high spatiotemporal resolution and penetration depth due to the reduced tissue autofluorescence and decreased photon scattering at long wavelengths. Although small organic SWIR dye molecules have excellent biocompatibility, they have been rarely exploited as compared to their inorganic counterparts, mainly due to their low quantum yield. To increase their brightness, in this work, the SWIR dye molecules are placed in close proximity to gold nanorods (AuNRs) for surface plasmon‐enhanced emission. The fluorescence enhancement is optimized by controlling the dye‐to‐AuNR number ratio and up to ≈45‐fold enhancement factor is achieved. In addition, the results indicate that the highest dye‐to‐AuNR number ratio gives the highest emission intensity per weight and this is used for synthesizing SWIR imaging probes using layer‐by‐layer (LbL) technique with polymer coating protection. Then, the SWIR imaging probes are applied for in vivo imaging of ovarian cancer and the surface coating effect on intratumor distribution of the imaging probes is investigated in two orthotopic ovarian cancer models. Lastly, it is demonstrated that the plasmon‐enhanced SWIR imaging probe has great potential for fluorescence imaging‐guided surgery by showing its capability to detect sub‐millimeter‐sized tumors.

Epigenetic Metal‐Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective Chemo‐Metalloimmunotherapy in Platinum‐Resistant Ovarian Cancer

ABSTRACT Platinum‐resistant ovarian cancer (PROC) responds poorly to platinum chemotherapy and evades immune surveillance by suppressing the cGAS‐STING pathway, leading to poor outcomes. Herein, we developed an epigenetic metal‐organic framework (MOF) nanoagonist (CMZ‐Pt‐SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn‐ZIF‐8 encapsulating CaO 2 and co‐loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ‐Pt‐SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO 2 triggers calcium overload and oxygen release, and Mn 2+ /Zn 2+ enhances oxidative stress and STING signaling, collectively strengthening chemo‐metalloimmunotherapy. These mechanisms intensify CisPt‐induced DNA damage and stimulate immune activation. CMZ‐Pt‐SA@HA applies a three‐step “POP” strategy to overcome PROC's triple defenses: (I) Pre‐targeting to enhance DNA‐CisPt adducts; (II) On‐targeting to block DNA repair; and (III) Post‐targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS‐STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient‐derived xenograft mouse models, or combined with anti‐PD‐L1 therapy in ascites metastasis models, CMZ‐Pt‐SA@HA consistently showed strong therapeutic efficacy. Its Mn 2+ ‐based magnetic resonance imaging (MRI) capability further supports image‐guided therapy and clinical translation.

Near Infrared‐Fluorescent Dinuclear Iridium(III) Nanoparticles for Immunogenic Sonodynamic Therapy

AbstractDinuclear iridium(III) complexes activated by light‐inducible spatiotemporal control are emerging as promising candidates for cancer therapy. However, broader applications of current light‐activated dinuclear iridium(III) complexes are limited by the ineffective tissue penetration and undesirable feedback on guidance activation. Here, an ultrasound (US) triggered near infrared‐fluorescent dinuclear iridium(III) nanoparticle, NanoIr, is first reported to precisely and spatiotemporally inhibit tumor growth. It is demonstrated that reactive oxygen species can be generated by NanoIr upon exposure to US irradiation (NanoIr + US), thereby inducing immunogenic cell death. When combined with cisplatin, NanoIr + US elicits synergistic effects in patient‐derived tumor xenograft mice models of ovarian cancer. This work first provides a design of dinuclear iridium(III) nanoparticles for immunogenic sonodynamic therapy.

Polymer‐PARPi Conjugates Delivering USP1i for Maximizing Synthetic Lethality to Stimulate STING Pathway in High‐Grade Serous Ovarian Cancer

Abstract Overcoming the immunosuppressive tumor microenvironment and therapeutic resistance remains a significant challenge in ovarian cancer treatment. In this study, a glutathione‐responsive polymeric nanoparticle platform for the co‐delivery of the USP1 inhibitor SJB3‐019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione‐responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8⁺ T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.

Gambogic Acid Based Coordination Polymer Reinforces High‐Intensity Focused Ultrasound Treatment of Gynecologic Malignancies

AbstractHigh‐intensity focused ultrasound (HIFU) is emerging as a promising non‐invasive treatment for solid tumors. Nevertheless, HIFU may also induce the upregulation of Heat Shock Protein 90 (HSP‐90), potentially resulting in resistance to HIFU. Besides, although it is effective against in situ tumors, challenges remain with tumor metastasis and recurrence. Herein, the innovative design of gambogic acid (GA) based coordination polymer—GAZn‐PEG nanoparticles (GAZn‐PEG NPs) are synthesized through the coordination of GA with zinc ions (Zn2+), and subsequently functionalized with lipid bilayer incorporating polyethylene glycol (PEG), sensitizing HIFU for the treatment of cervical and ovarian cancers. Briefly, under HIFU exposure, GA markedly suppresses the expression of HSP‐90, thereby increasing the tumor's sensitivity to HIFU therapy. Furthermore, Zn2+ not only overcome the issue of GA's poor water solubility but also synergistically stimulate immune responses in conjunction with GA. More intriguingly, it has been discovered that GAZn‐PEG can effectively activate the cyclic GMP‐AMP synthase‐stimulator of the interferon genes (cGAS‐STING) pathway, thereby enhancing the immune responses provoked by HIFU. Specifically, GAZn‐PEG NPs show a remarkable increase in dendritic cell activation and the effective stimulation of the cGAS‐STING pathway, crucial for long‐term protection against tumor recurrence and metastasis.

Quinoidal Semiconductor Nanoparticles for NIR‐II Photoacoustic Imaging and Photoimmunotherapy of Cancer

AbstractPhotoagents with ultra‐high near‐infrared II (NIR‐II) light energy conversion efficiency hold great promise in tumor phototherapy due to their ability to penetrate deeper tissues and minimize damage to surrounding healthy cells. However, the development of NIR‐II photoagents remain challenging. In this study, an all‐fused‐ring quinoidal acceptor‐donor‐acceptor (A‐D‐A) molecule, SKCN, with a BTP core is synthesized, and nanoparticles named FA‐SNPs are prepared. The unique quinoidal structure enhances π‐electron delocalization and bond length uniformity, significantly reducing the bandgap of SKCN, resulting in strong NIR‐II absorption, a high molar extinction coefficient, and a photothermal conversion efficiency of 75.14%. Enhanced molecular rigidity also facilitates efficient energy transfer to oxygen, boosting reactive oxygen species generation. By incorporating the immunomodulator R848, FA‐SRNPs nanoparticles are further developed, effectively modulating the tumor immune microenvironment by reducing Tregs and M‐MDSCs infiltration, promoting dendritic cell maturation, M1 macrophage polarization, and activating CD8+ T cells and NK cells. Comprehensive studies using orthotopic ovarian cancer models demonstrated strong tumor targeting, photoacoustic imaging capabilities, and significant tumor suppression and metastasis inhibition, and also showing excellent therapeutic efficacy in an orthotopic breast cancer model. This study provides strong evidence for the potential application of quinoidal A‐D‐A molecules in cancer photoimmunotherapy.

In Situ Nanofiber Formation Blocks AXL and GAS6 Binding to Suppress Ovarian Cancer Development

AbstractAnexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off‐target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap‐Phe‐Phe‐Glu‐Ile‐Arg‐Leu‐Arg‐Phe‐Lys (Nap‐IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap‐IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor‐instructed nanoparticle‐to‐nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap‐IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap‐IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap‐IR can be applied in clinical ovarian cancer therapy in the near future.

pH‐Responsive Biomineralized Probiotic for Self‐Amplifying Mucosal Vaccination: Gut‐Engineered Antigen Factories Drive Targeted Cervical Tumor Regression

Abstract Therapeutic vaccines against cervical cancer critically depend on sustained high‐level HPV antigen production and prolonged antigen exposure. However, suboptimal antigen bioavailability and rapid systemic clearance remain key barriers to achieving robust vaccine efficacy. Here, we engineer an oral biohybrid vaccine using pH‐responsive biomineralized Bacillus subtilis (B‐BS/E7@M) to establish gut‐based antigen factories for sustained HPV16 E7 production. The calcium phosphate mineral coating confers gastric acid resistance (78.9% survivability vs. 9.1% uncoated) and synergizes with probiotic‐mucosa interactions to prolong intestinal retention (96 h, 4 × controls), enabling >4‐day antigen persistence and markedly enhances oral bioavailability. This system elicits coordinated immune activation: mucosal priming through germinal center expansion and APC maturation elevates IgG, IgA, and T‐cell subsets—including total T cells, cytotoxic T cells, and effector memory T cells—from day 21 onward. Systemic CD8 + T‐cell activation via cross‐presentation enhances central and effector memory T cells, promoting tumor infiltration and resulting in 64% tumor suppression ( p < 0.001) with 50% complete remission in TC‐1 models. Mechanistic studies pinpoint gut‐orchestrated cytotoxic T cell clonal expansion as the dominant effector pathway. By bridging synthetic biology with stimuli‐responsive biomaterials, this work pioneers a paradigm of living biotherapeutics—self‐replicating, mucosa‐deployable systems for precision cancer immunotherapy.

An Acceptor–Donor–Acceptor Structured Nano‐Aggregate for NIR‐Triggered Interventional Photoimmunotherapy of Cervical Cancer

AbstractCompared with conventional therapies, photoimmunotherapy offers precise targeted cancer treatment with minimal damage to healthy tissues and reduced side effects, but its efficacy may be limited by shallow light penetration and the potential for tumor resistance. Here, an acceptor–donor‐acceptor (A‐D‐A)‐structured nanoaggregate is developed with dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), triggered by single near‐infrared (NIR) light. Benefiting from strong intramolecular charge transfer (ICT), the A–D–A‐structured nanoaggregates exhibit broad absorption extending to the NIR region and effectively suppressed fluorescence, which enables deep penetration and efficient photothermal conversion (η = 67.94%). A suitable HOMO–LUMO distribution facilitates sufficient intersystem crossing (ISC) to convert ground‐state oxygen (3O2) to singlet oxygen (1O2) and superoxide anions (·O2−), and catalyze hydroxyl radical (·OH) generation. The enhanced ICT and ISC effects endow the A–D–A structured nanoaggregates with efficient PTT and PDT for cervical cancer, inducing efficient immunogenic cell death. In combination with clinical aluminum adjuvant gel, a novel photoimmunotherapy strategy for cervical cancer is developed and demonstrated to significantly inhibit primary and metastatic tumors in orthotopic and intraperitoneal metastasis cervical cancer animal models. The noninvasive therapy strategy offers new insights for clinical early‐stage and advanced cervical cancer treatment.

A Tumor‐Targeted tRF Therapeutics Triggers Ovarian Cancer Ferroptosis via Dual Inhibition of System Xc −

ABSTRACT The severe chemoresistance‐caused high recurrence has made ovarian cancer (OVCA) the most lethal gynecological malignancy in clinical practice. Ferroptosis represents a promising therapeutic approach for OVCA, which could effectively overcome tumor resistance. Nevertheless, the traditional ferroptosis inducers lack specificity and selectivity, resulting in poor therapeutic effects. Here, we identified a novel tRNA‐derived fragment, tRF‐21‐XSXMSL73E (tRF‐21), which could serve as a ferroptosis inducer to efficiently suppress OVCA growth through dual inhibition of the system Xc − /glutathione (GSH)/peroxidase 4 (GPX4) axis without causing obvious side effects. Mechanistically, tRF‐21 promotes SLC3A2 ubiquitination via SPOP E3 ligase and destabilizes SLC7A11 mRNA by disrupting NSUN2‐mediated m 5 C methylation. This dual‐inhibition effect on the system Xc − /GSH/GPX4 axis leads to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death. To enhance therapeutic delivery, we engineered a pH‐responsive nanoplatform (tRF‐21@EPH) with an ellagic acid core, polyetherimide (PEI) intermediate layer, and hyaluronic acid shell, enabling nuclease protection and tumor‐specific uptake. This system markedly improved tRF‐21 efficacy with minimal toxicity, providing a novel RNA‐based strategy for OVCA treatment.

Specific and Long‐Term Luminescent Monitoring of Hydrogen Peroxide in Tumor Metastasis

AbstractLuminescent monitoring of endogenous hydrogen peroxide (H2O2) in tumors is conducive to understanding metastasis and developing novel therapeutics. The clinical transformation is obstructed by the limited light penetration depth, toxicity of nano‐probes, and lack of long‐term monitoring modes of up to days or months. New monitoring modes are introduced via specific probes and implantable devices, which can achieve real‐time monitoring with a readout frequency of 0.01 s or long‐term monitoring for months to years. Near‐infrared dye‐sensitized upconversion nanoparticles (UCNPs) are fabricated as the luminescent probes, and the specificity to reactive oxygen species is subtly regulated by the self‐assembled monolayers on the surfaces of UCNPs. Combined with the passive implanted system, a 20‐day monitoring of H2O2 in the rat model of ovarian cancer with peritoneal metastasis is achieved, in which the limited light penetration depth and toxicity of nano‐probes are circumvented. The developed monitoring modes show great potential in accelerating the clinical transformation of nano‐probes and biochemical detection methods.

Transforming the Chemical Structure and Bio‐Nano Activity of Doxorubicin by Ultrasound for Selective Killing of Cancer Cells

AbstractReconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor‐selective drugs. Here, as a proof‐of‐concept, the use of high‐frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self‐aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug‐resistant cell lines. Only marginal cytotoxicity (80–100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25–40 µg mL−1). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor‐mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell‐collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono‐active moieties.