In Vivo Programmed Assembly of Polymer–Peptide Conjugates to Overcome Multistage Drug Delivery Barriers

Surmounting the cascade of biological barriers to efficient drug delivery is a central challenge in oncology. Here, we design a polymer-peptide conjugate (PPC) as an intelligent nanodrug capable of in vivo programmed assembly. The PPC system, responsive to both ultrasound (US) and acidic pH, demonstrates tunable size and charge for on-site disassembly and reassembly. Specifically, to facilitate deep tumor penetration, PPC nanoparticles disassemble into free molecules upon ultrasound stimulation at the tumor periphery. Subsequently, the negatively charged motifs reassemble into positively charged nanoparticles, triggered by the acidic tumor microenvironment, promoting endocytosis and mitochondrial damage-induced apoptosis. This approach achieves a 12-fold improvement in tumor penetration efficiency and an 8.8-fold increase in cellular uptake. Our work advances the design of intelligent nanodrugs and enhances the precision of drug delivery.