Dual‐Locked Polymeric STING Nano‐Agonist/Sonosensitizer Augments Spatiotemporally Controlled Cancer Sono‐Immunotherapy

The stimulator of interferon genes (STING) pathway is a central target in cancer immunotherapy, but current STING agonist therapies lack precision control, leading to suboptimal therapeutic outcomes and systematic adverse effects. Herein, we engineered a dual‐locked immuno‐polymeric nanoplatform (IPN) with precise spatiotemporal control over the release of STING agonists to enhance cancer immunotherapy. This platform, constructed from biocompatible poly(β‐amino esters) (PBAE), incorporates the STING agonist (MSA‐2) covalently linked via ester bonds, which is co‐assembled with a sonosensitizer. Upon activation by ultrasound and natural esterase enzyme, IPN significantly enhances the localized release of MSA‐2 within the tumor. Alongside, this platform augments the generation of toxic radicals, leading to the spread of tumor antigens and immunogenic biomolecules, subsequently initiating a high magnitude of antigen‐specific T cells for tumor eradication. The multifaceted advantages of ultrasound and enzymes synergistically enhance the physical contact and spatial organization of immune‐related reactants as well as chemical bioprocesses. This dual‐locked IPN platform demonstrates an eight fold greater tumor inhibition compared to single‐locked counterparts and a four fold enhancement over the summation effect, highlighting a safer and more effective paradigm for cancer immunotherapy.