A Self-Adjuvanting Nanovaccine with Ultrasound-Synchronized Activation for Coordinated Innate and Adaptive Antitumor Immunity

Immunotherapy has demonstrated considerable potential in cancer treatment; however, it continues to face persistent challenges such as tumor heterogeneity, immunosuppressive microenvironments, and inefficient delivery of immunomodulators. To overcome these limitations, we develop a self-adjuvanting nanovaccine (NVMP) that incorporates the following key components: (1) covalent conjugation of the STING agonist MSA-2 to a model neoantigen, (2) a semiconducting polymer (PF8DPP) for sonodynamic therapy, and (3) a reactive oxygen species (ROS)-responsive nanoparticle shell. With ultrasound (US) irradiation, PF8DPP produces ROS, which induces localized immunogenic cell death (ICD) and cleaves the ROS-responsive shell to promote the intratumoral release of antigen-adjuvant conjugates. The covalent linkage between the antigen and adjuvant ensures the synchronous uptake and activation within antigen-presenting cells (APCs), followed by glutathione (GSH)-mediated release of MSA-2. This strategy enables dual-pathway immune activation via combining STING agonism with ICD-derived damage-associated molecular patterns (DAMPs). In B16-OVA melanoma models, NVMP exhibits superior therapeutic efficacy, significantly suppressing primary tumor growth and eliciting robust systemic immunity that effectively inhibits metastasis. The spatially confined, US-triggered activation mechanism will minimize off-target toxicity. Thus, NVMP represents a paradigm-shifting platform that facilitates coordinated codelivery of antigen and adjuvant, STING activation, and US-enhanced remodeling of the tumor microenvironment for cancer therapy.