Design, Synthesis, and Acid‐Responsive Disassembly of Shell‐Sheddable Block Copolymer Labeled with Benzaldehyde Acetal Junction.

Smart nanoassemblies degradable through the cleavage of acid‐labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid‐degradable shell‐sheddable nanoassemblies. Herein, the authors report the synthesis and acid‐responsive degradation through acid‐catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid‐labile linkage. The authors explore the synthesis and aqueous micellization of well‐defined poly(ethylene glycol)‐based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally‐stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid‐catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid‐degradable shell‐sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid‐degradable shell‐sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor‐targeting drug delivery. [ABSTRACT FROM AUTHOR]