Ultrasound-activated in situ nano-vaccines (SATNAV) for precise CRPC sono-immunotherapy via multi-reprograming the immunosuppressive microenvironment

Ultrasound (US) -responsive therapy shows promise for castration-resistant prostate cancer (CRPC), which is associated with high mortality and limited treatment options. Especially, the combination of sono-triggered local tumor destruction with immunotherapy may offer synergistic benefits, while the efficacy of such sono-immunotherapy is hindered by the inherently “immune-cold” tumor microenvironment (TME) of CRPC. Herein, a sono-triggered in situ nano-vaccine (SATNAV) is developed for precise CRPC sono-immunotherapy via multi-reprograming the immunosuppressive TME. On one hand, under high-intensity focused ultrasound (HIFU) irradiation, the perfluoropentane (PFP)-containing SATNAV undergoes acoustic droplet vaporization and cavitation, realizing satisfactory ablation of solid tumors and producing an in-situ vaccine effect with immunogenic cell death (ICD). On the other hand, the immunosuppressive microenvironment of CRPC is regulated in multiple aspects for a favorable prognosis. SATNAV improves tumor-selective accumulation by Neuropilin-2 (NRP-2)-targeted recognition and may help attenuate secretory immune evasion associated with exosomal programmed death-ligand 1 (PD-L1). Moreover, SATNAV delivers a redox-responsive stimulator of interferon genes (STING) agonist (MSA-2) to immunosuppressive regions and collaborates with sono-triggered to achieve immune activation. This system suppresses exosomal PD-L1-related immune escape, activates the STING-TBK1-IRF3 pathway, and enhances immune cell infiltration, thereby suggesting the potential to induce immunological memory and ultimately multi-remodel the immunosuppressive TME of CRPC. SATNAV represents a novel strategy that integrates sono-triggered cavitation ablation with immune activation for CRPC treatment.