Engineered Macrophages Tune Intratumoral Cytokines through Precisely Controlled Self‐Pyroptosis to Enhance Bladder Cancer Immunotherapy

Abstract Engineered macrophages are a promising tool for drug delivery and immunotherapy in cancer treatment. However, simultaneous targeted enrichment and controllable immunological activation of these macrophages at the tumor site remains challenging. As a solution, macrophages loaded with an advanced nanoparticle encapsulating CpG‐conjugated magnetic nanoclusters (MNC) with indocyanine green (ICG) and nigericin (NIG) (MNC‐ICG‐NIG@SiO 2 (MINS)), utilizing Se─Se bond‐modified SiO 2 , are designed and applied in bladder cancer, which is typically managed surgically, followed by Bacillus Calmette–Guerin (BCG) adjuvant instillation therapy. Upon intravenous administration, BCG‐mediated tumor‐localized inflammation leads to targeted accumulation of MINS@MΦ. MINS@MΦ accumulates within the tumor tissue and is immunologically activated through laser irradiation, leading to ICG‐mediated generation of reactive oxygen species, Se─Se bond cleavage, and subsequent NIG release to induce self‐pyroptosis. Consequently, MINS@MΦ releases Fe 2+ ions and CpG, thus promoting the M1 polarization of tumor‐associated macrophages and secretion of appropriate antitumor cytokines. However, without intervention, MINS@MΦ undergoes apoptosis in the bloodstream after 48 h without eliciting any immune response. Therefore, this innovative approach optimizes and enhances the efficacy of BCG immunotherapy by precisely modulating the cytokines for effective bladder cancer treatment without inducing a systemic inflammatory response.