Ratio‐Tunable Dual‐Peptide and Ultrasound‐Assisted Nanoplatform for Enhancing Personalized Antitumor Immunotherapy

ABSTRACT Immune checkpoint‐based immunotherapy has become a central strategy for treating solid tumors by restoring endogenous antitumor immunity. However, clinical responses remain limited and highly variable across patients and tumor types because co‐existing inhibitory pathways are engaged to different extents, while current therapies generally rely on fixed targeting architectures and are not designed to accommodate patient specific checkpoint dependence. Here, we developed ratio tunable bispecific nanoparticles (BiNPs) for personalized immune checkpoint‐based immunotherapy by co‐assembling an aggregation induced emission sonosensitizer core with two β‐sheet self‐assembling peptides, Pep@CD47 and Pep@PD‐L1, enabling programmable control of peptide stoichiometry. BiNPs promote lysosomal internalization and degradation of CD47 and PD‐L1 through a lysosome targeting chimera inspired process, and ultrasound‐activated sonodynamic therapy generates reactive oxygen species to induce immunogenic cell death with calreticulin exposure and ATP and HMGB1 release. In syngeneic SCC‐7 tumor models, ultrasound‐activated BiNPs with a selected peptide ratio enhance dendritic cell maturation, shift macrophages toward an M1‐like phenotype, increase CD8 + T cell infiltration, and suppress primary and distant tumors with favorable biosafety. Ex vivo screening of freshly resected HNSCC specimens identifies distinct optimal Pep@CD47: Pep@PD‐L1 ratios among patients, demonstrating that BiNPs offer a personalized approach for effective immunotherapy across heterogeneous solid tumors.