Programmed Cascade Polydopamine Nanoclusters for Pyroptosis‐Based Tumor Immunotherapy

Abstract Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti‐tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti‐tumor immunotherapy. Herein, a pH‐responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo‐arginine (R 8 )‐1‐Hexadecylamine (He)‐porphyrin (Por)@PDA‐gambogic acid (GA)‐cRGD (R‐P@PDA‐GC), is rationally design to augment phototherapy‐induced pyroptosis and boost anti‐tumor immunity through a two‐input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R 8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R‐P@PDA‐GC nanoplatforms (NPs). The pH‐responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two‐input programmed irradiation, R‐P@PDA‐GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase‐1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8 + T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti‐tumor immunity.