NO‐Enhanced Sonodynamic Nanovesicles with Co‐Stimulatory Molecule Self‐Presentation for Multidimensional Tumor Immunotherapy

Synergistically improving T cell responsiveness represents a promising therapeutic strategy for tumors; however, current treatments struggle to fully activate cancer-immunity cascade. We propose a novel gas-assisted sonosensitizer-loaded biomimetic nanoplatform, triggering ultrasonic-sensitive tumor immunogenic cell death (ICD) and cascading immune activation. Upon ultrasound stimulation, the nanocore liberates reactive oxygen species and nitric oxide, generating highly toxic peroxynitrite (ONOO^-) in situ. The ONOO^- then orchestrated several intracellular events, including protein S-nitrosylation, endoplasmic reticulum stress, Ca²⁺ dyshomeostasis-mediated mitochondrial dysfunction, and ICD-enhanced immune cell recruitment. Furthermore, the biomimetic artificial dendritic cell (DC) membranes, from genetically engineered tumor cells, simultaneously present peptide-major histocompatibility complex class I (pMHC-I) and CD86, enabling homologous tumor targeting but also mimicking the antigen presentation and costimulatory signaling of DCs to directly activate infiltrating T lymphocytes. In multiple murine models, this nanovaccine demonstrated remarkable therapeutic efficacy, including tumor suppression, long-lasting antitumor immunity, and tumor metastasis inhibition. The ultrasound-responsive nanoDCs offer a promising paradigm for multifaceted immune boosters to address the challenges of immune tolerance and suboptimal patient response.