Hydrolytically Degradable Polyethylene Glycol Bottlebrush Polymers Address the Stability-Clearance Trade-Off for Drug Delivery.

Long-circulating polyethylene glycol bottlebrush polymers (BrushPEG) are attractive drug carriers, but their nondegradable backbones cause persistent tissue retention, raising concerns about long-term safety and clinical translation. Here, we report a hydrolytically degradable PEG bottlebrush polymer (D-BrushPEG) created by incorporating 7-oxa-2,3-diazanorbornene (ODAN) units into the backbone. D-BrushPEG retains prolonged circulation (elimination half-life ≈24.7 h, compared with ≈0.78 h for a small-molecule dye) while undergoing controlled hydrolysis that greatly improves systemic and tissue clearance. More than 99% of the circulating signal is removed within 13 days, accompanied by a near-complete loss of liver and skin fluorescence. In contrast, a nondegradable BrushPEG analog exhibits slower plasma elimination (∼5% remaining at day 13) and persistent accumulation in the liver and skin for over one month. When conjugated with gemcitabine (GEM) through a reduction-responsive self-immolative linker, D-BrushPEG demonstrated comparable antitumor efficacy to the nondegradable BrushPEG-GEM formulation. Systemic evaluation indicates comparable hepatic and renal safety profiles for both polymers, with only mild renal changes observed, while skin irritation is reduced for D-BrushPEG relative to BrushPEG. These results demonstrate that controlled backbone hydrolysis allows PEG bottlebrush polymers to balance long circulation with efficient clearance, reducing tissue persistence and the risk of side effects.