A Self-Amplifying Ultrasound-Activated Polymeric Prodrug Nanoplatform for Synergistic Sonodynamic Immunotherapy

Ultrasound (US)-triggered sonodynamic therapy (SDT) combined with immunotherapy shows considerable promise, yet its therapeutic efficacy remains constrained by insufficient intratumoral drug activation and limited immunogenicity. Herein, we report a self-amplifying US-responsive nanoplatform (PMB@R848) for synergistic sonodynamic immunotherapy. The nanotherapeutic was constructed by conjugating the sonosensitizer methylene blue (MB) to polylysine through US-labile urea-based linkages, providing a stable framework for efficient complexation of immunostimulant R848. Under physiological conditions, PMB@R848 exhibited excellent colloidal stability and biocompatibility. Upon US irradiation, the generated reactive oxygen species (ROS) initiated selective cleavage of urea bonds, exposing protonatable amino groups that enhanced intraparticle electrostatic repulsion under mildly acidic tumor microenvironment. This cascade process further accelerated nanoparticle destabilization and established a self-amplified release behavior, enabling synchronized liberation of both MB and R848. The released MB markedly enhanced ROS generation, inducing robust immunogenic cell death and tumor antigen release, while R848 further amplified dendritic cell maturation and systemic antitumor immunity. Benefiting from the synergistic integration of self-amplified SDT and immune activation, PMB@R848 achieved potent inhibition of primary tumors, effectively suppressed recurrence, and established durable immune memory in multiple murine tumor models. This work presents a self-amplifying, US-activatable nanoplatform for precision sonodynamic immunotherapy.