In Situ Secondary Self‐Assembly of Near‐Infrared II J‐Aggregates: A Novel Phototheranostic Strategy for Inducing Tumor Pyroptosis

Pyroptosis, a programmed cell death mechanism that bypasses apoptosis resistance and triggers tumor-specific immune responses, has gained much attention as a promising approach to cancer therapy. Despite enhancing tumor accumulation and extending the circulation of small-molecule drugs, nanomedicines still face significant challenges, including poor tissue penetration, tumor resistance, and hypoxic microenvironments. To overcome these challenges, a novel near-infrared II (NIR-II) J-aggregate-based nanomedicine is designed, leveraging an in situ secondary self-assembly strategy to fabricate highly targeted nanoparticles (MSDP NPs). These nanomedicines trigger pyroptosis by generating type I reactive oxygen species, especially superoxide anions, while simultaneously activating photoimmunotherapy. In vivo studies demonstrate that MSDP NPs achieve efficient tumor penetration and prolong tumor retention, which is facilitated by the J-aggregate-driven formation of microscale spindle-shaped fibrillar bundles through in situ secondary self-assembly at the tumor site. This unique structural transformation enhances nanomedicine accumulation in tumor tissues, enabling robust NIR-II fluorescence imaging and improving therapeutic efficacy even in hypoxic tumor microenvironments. This study provides an innovative phototheranostic strategy that utilizes the in situ secondary self-assembly of NIR-II J-aggregates to induce tumor pyroptosis, offering a potential solution to the limitations of current nanomedicines in cancer therapy.