Multi-Responsive Bottlebrush-Like Unimolecules Self-Assembled Nano-Riceball for Synergistic Sono-Chemotherapy

Improved drug loading content, bioavailability, and controlled release in targeted tissue have been major bottlenecks in the design of precision nanomedicine. Herein, a tumor-specific and multiple-stimuli responsive nano-riceball is proposed and validated for enhanced sono-chemotherapy. The nano-riceball (NGR@DDP) possesses a well-designed core-shell structure, formed by an inner core assembly that contains ultrasound/H₂ O₂ responsive bottlebrush-like unimolecular dextran-POEGMA₉ -b-PMTEMA₂₂ (DOS) with co-loaded doxorubicin and Purpurin 18. This inner core of NGR@DDP is further buried by a "striffen" of NGR (Asn-Gly-Arg)-modified RBC-membrane derived from CRISPR-engineered mice. As a result, nano-riceball NGR@DDP is featured with high drug stuffing content (30.3 wt%), low critical micelle concentration (5.93 µg mL^-1 ), and intelligent exogenous ultrasound/endogenous H₂ O₂ stimuli-triggered precise drug release at tumor site. Under fluorescence/photoacoustic imaging guidance, combined sonodynamic therapy and chemotherapy exhibit excellent synergistic effect, and dramatically inhibit the growth of orthotopic HepG2 hepatocellular carcinoma with negligible side effects. This nano-riceball strategy provides a facile way to achieve function hybridization for personalized nanomedicine.