Upper Critical Solution Temperature Polymer, Photothermal Agent, and Erythrocyte Membrane Coating: An Unexplored Recipe for Making Drug Carriers with Spatiotemporally Controlled Cargo Release

"On-demand" drug release within target site is critical for targeted drug delivery systems. We herein integrate the advantages of upper critical solution temperature (UCST) polymers, photothermal agent, and red blood cell (RBC) membrane coating into a single drug delivery nanosystem and, for the first time, achieve remotely controlled UCST polymer-based drug delivery system that undergoes "on-demand" drug release within specified zone. When in laser-off state, the resulting nanosystem demonstrates significantly diminished drug self-leakage, owing to shielding by the RBC membrane coating. Upon laser irradiation, this system undergoes responsive drug release, likely because of particle swelling due to its UCST polymer component's hydrophobic-to-hydrophilic transition triggered by the rapid localized heating generated by its preloaded photothermal agent via photothermal effects. As a result, this drug delivery system exhibits spatiotemporally controlled cytotoxicity to cultured cells, efficiently eradicating irradiated cancerous cells without appreciably impacting nonirradiated ones, those ∼0.7 cm away from the irradiation zone. This work may open an avenue to thermosensitive drug delivery systems potentially "ideal" for intravenous administration and inspire future efforts on biomedical applications of UCST polymers.