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/H2O2 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 H2O2 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.