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

Abstract

Abstract 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, Ca 2+ 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.