AIE-Augmented NIR-II-Emissive Supramolecular Metallacycle Nanoplatform for Tumor Microenvironment-Responsive Chemo-Photothermal-Immunotherapy.

Abstract

The integration of multimodal therapies into a single nanoplatform promises significant advances in precision oncology, yet structural instability, premature drug leakage, and insufficient immune activation remain key challenges. Herein, a supramolecular metallacycle-based nanoplatform (M2S-AD NPs) is engineered through coordination-driven self-assembly and β-cyclodextrin-mediated host-guest encapsulation. The metallacycle exhibits aggregation-induced emission (AIE) characteristics to amplify NIR-II fluorescence (1084 nm) for real-time tumor imaging and achieves a record-high photothermal conversion efficiency (42.7%) under 808 nm irradiation, enabling deep-tissue photothermal ablation. Leveraging tumor microenvironment (TME)-responsive disulfide bonds and pH-labile Pt-N coordination, M2S-AD NPs selectively release chemotherapeutic agents in glutathione-rich tumors while maintaining stability under physiological conditions. Synergistically, localized hyperthermia induces immunogenic cell death, releasing tumor antigens to prime dendritic cells, while co-delivered anti-PD-L1 antibodies reverse immunosuppression, amplifying cytotoxic T lymphocyte infiltration. In 4T1 breast tumor models, this combinatorial strategy eradicates primary tumors and suppresses distant metastases with >80% tumor growth inhibition without inducing systemic toxicity. By unifying AIE-enhanced imaging, TME-triggered drug release, and immunomodulation, this work establishes a supramolecular engineering paradigm for next-generation cancer theranostics, bridging material innovation with immunooncology to combat metastatic malignancies.