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.