Morphology control in benzoic imine-linked polymer-drug conjugates for adaptive drug delivery and enhanced in vivo efficacy

• Engineering of PHPMAm copolymers with benzoic imine enabling stealth and pH-triggered drug release. • Spherical assemblies show 100% survival in murine lymphoma with high efficacy. • Alternative to PEG copolymers with tunable pH response, efficient drug delivery, and low toxicity. Nanomedicines have shown significant potential in advancing treatment for a variety of cancer types. Despite these advances, further research is essential to improve the efficacy and selectivity of anticancer nanomedicines, particularly by developing delivery systems capable of achieving high efficacy with minimal off-target toxicity. We herein report novel pH-responsive block copolymer-drug conjugates based on poly( N -(2-hydroxypropyl)methacrylamide) (PHPMAm) and benzoic imine linkages, uniquely combining stealth performance with tunable, acid-triggered drug release. By engineering block and random copolymer architectures with controlled hydrophilic shell length, we systematically evaluated how polymer structure governs self-assembly, release kinetics, and therapeutic outcomes. The conjugates achieve up to 10–12 wt% doxorubicin loading, with pH-selective release half-live spanning within 2–40 h. In contrast to most Schiff base polymer-drug systems limited to in vitro data, the synthesized polymer-drug conjugates demonstrated outstanding antitumor efficacy and 100 % survival for spherical assemblies in aggressive murine lymphoma models, with superior safety. Unlike conventional PEG systems, PHPMAm-based copolymers can potentially avoid anti-PEG immunogenicity and exhibit exceptional in vivo stability and tumor accumulation.