Boronate ester can be used to prepare intelligent polymer nanoparticles (NPs). However, the traditional boronate ester polymer NPs made of boronic acid and diols using a "single-lock" strategy (B−O NPs) exhibit low drug loading capacity (DLC) and insufficient lysosomal escape ability, resulting in limited antitumor efficacy. We develop a "two-lock" strategy that combines dodecanamine and boronic acid using boron−nitrogen (B ← N) coordination to enhance the formation of a boronate ester polymer. Through this strategy, amphiphilic dextran and poly(vinyl alcohol) are synthesized through conjugation with the phenylboronic acid (PBA)/dodecanamine complex. The amphiphilic dextran encapsulates paclitaxel (PTX) to form B−N−O NPs with a higher DLC than their "singlelock" compartments due to enhanced boronate ester stability and improved hydrophobic drug-polymer interactions. Moreover, the B−N−O NPs release more PTX under acidic conditions compared with the B−O NPs. To demonstrate the generality of this "twolock" strategy, eight polymer prodrug B−N−O NPs employing poly(vinyl alcohol) or dextran, along with PBA-modified gemcitabine, fluorouracil, and 7-ethyl-10-hydroxycamptothecin, or boronic acid-containing bortezomib and dodecanamine, are prepared, showing overall enhanced DLC and higher responsive drug release efficiency compared to B−O NPs. Importantly, B−N− O NPs with a combination of dodecanamine and boronic acid show a better lysosomal escape capability than B−O NPs. Moreover, B−N−O NPs exhibit stronger cytotoxicity compared to B−O NPs and free drugs in vitro.Their enhanced drug loading, responsive drug release, and lysosomal escape abilities contribute to enhanced antitumor efficacy in vivo. This "two-lock" strategy can be a general and convenient method to prepare responsive polymer NPs with enhanced anticancer efficacy.
