NIR-II imaging-guided nanoplatform for synergistic mitochondria-targeted pyroptosis and macrophage reprogramming immunotherapy.

Cancer immunotherapy has revolutionized modern oncology by mobilizing the body's immune system, yet its efficacy remains severely limited in immunologically "cold" tumors, which are defined by poor immune infiltration and low tumor immunogenicity. Here, we report a multi-functional nanoplatform that integrates a new second near-infrared (NIR-II) aggregation-induced emission luminogen (AIEgen), a mitochondria-targeted lonidamine prodrug, and cryo-shocked M1 macrophage membranes (CSMs) to achieve synergistic tumor microenvironment (TME) reprogramming and precision image-guided immunotherapy. The bright NIR-II AIEgen enables high-resolution fluorescence and photoacoustic imaging for real-time tumor visualization and photothermal therapy. The prodrug LND-1-PEG-24, cleavable by TME-overexpressed cathepsin B, preferentially accumulates in mitochondria to trigger caspase-3/GSDME-mediated pyroptosis, leading to the release of danger-associated molecular patterns that markedly enhance tumor immunogenicity. Simultaneously, CSMs promote durable polarization of tumor-associated macrophages (TAMs) toward the tumoricidal M1 phenotype via the TLR2/MAPK pathway, thereby alleviating TME immunosuppression. In tumor-bearing mice, this nanoplatform synergistically enhances cytotoxic T cell infiltration, reverses immune suppression, and effectively inhibits both primary tumor growth and metastatic progression through the activation of systemic antitumor immunity. This work establishes a versatile strategy that unifies NIR-II phototheranostics, mitochondria-targeting pyroptosis, and TAM reprogramming, providing a robust and targeted approach for cancer immunotherapy.