Unimolecule-based size-charge switchable nanomedicine for deep cancer sono-immunotherapy.

• Unimolecule-based size-charge switchable nanomedicine is of importance for precision medicine. • Assembly and disassembly mechanism of unimolecular micelles for enhancing nanoparticle in tumor accumulation and penetration. • Acid-responsive unimolecular micelles with enhanced tumor penetration and dual immunization strategies for synergistic sono-immunotherapy. [Display omitted] Immune checkpoint inhibitor-based immunotherapy has been the most promising method for treating cancer patients. In this study, an anti-programmed death ligand 1 peptide inhibitor (APP) was engineered to act in the inner core of unimolecular polymers (Dex-PCR780- b -P(DPA- co -APP). The APP polymers had the capability of forming nano-micelles (PCR780-APP NMs) via self-assembly and featured controlled exposure in an acidic microenvironment while maintaining APP original bioactivity. Notably, in an acid tumor microenvironment, the PCR780-APP NMs (~ 121.1 nm, 2.3 mV) quickly switched into ultrasmall and positively charged PCR780-APP unimolecular micelles (PCR780-APP UMs; ~ 24.1 nm, 19.6 mV) with ultrastability, a narrow polydispersity index, and great fluorescence/photoacoustic (FL/PA) linearity due to its unique and definite unimolecular structure. Based on these advantages, under FL/PA imaging guidance, size-charge switchable PCR780-APP NMs could control exposure of APP and when combined with ultrasound, induce specific-dosage reactive oxygen species (ROS) that facilitates abundant immune T-cell recruitment and activation in deep solid tumors. [ABSTRACT FROM AUTHOR]