1 Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec H4B 1R6, Canada.
2 Department of Physics, Concordia University, Montreal, Quebec H4B 1R6, Canada.
3 Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec H4B 1R6, Canada.

The development of acidic pH-responsive degradable amphiphilic block copolymers (ABPs) and their nanoassemblies has been extensively explored as a promising platform for tumor-targeting drug delivery and cancer therapy. Despite tremendous advances, most acidic pH-degradable ABP nanoassemblies have been designed with acid-labile groups positioned in a single location, such as the hydrophobic core or at the core/corona interface, limiting their control over degradation and thus causing an inefficient release profile of encapsulated therapeutics. Herein, we report a dual-location acidic pH-responsive degradation strategy involving the synthesis of acidic pH-degradable ABP-based nanoassemblies bearing two different acid-labile linkages in hydrophobic cores and at interfaces that exhibit an individually controlled and synergistically enhanced release profile of encapsulated therapeutics. Well-defined ABPs are designed with benzaldehyde acetal at the block junction (e.g., interfaces) and conjugated benzoic imine in the hydrophobic block (e.g., cores), synthesized by reversible deactivation radical polymerization. Colloidally stable nanoassemblies formed through aqueous micellization have an acidic pH response desired for tumor-targeting drug delivery, e.g., slow degradation at pH = 6.5 (tumoral pH) and rapid degradation at pH = 5.0 (endo/lysosomal pH), while the remaining stable at pH = 7.3 (physiological pH). When loaded with curcumin anticancer drugs, nanoassemblies achieve a high encapsulation efficiency. Curcumin-loaded nanoassemblies exhibit enhanced curcumin release at endo/lysosomal pH levels. Moreover, they exhibit promising antitumoral activity and intracellular trafficking to cancer cells, while empty nanoassemblies are noncytotoxic. These results highlight the potential of the dual-location, acidic pH-responsive degradation strategy as a versatile platform for the next generation of tumor-targeted drug delivery.