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

Abstract 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.