Harnessing multicyclic topologies as biomimetic allostery with mechanical lysosome disruption properties for enhanced drug delivery

The leverage of synthetic polymer self-assemblies (SPSAs) as biomimetic allostery provides unique opportunities for developing bio-inspired soft species. However, the preparation of these soft species remains a challenge likely due to the synthetic difficulties toward SPSAs having four-level hierarchical structural transitions and the compromised colloidal stability of the self-assembled quaternary structures. Herein, we report self-assembly of topological polymers with hydrophilic multicycles (HMCs) for biomimetic allostery. Specifically, cationic copolymers containing HMCs are prepared via a reliable synthetic approach, whose hierarchical self-assembly affords stabilized nanoparticles that undergo biomimetic allostery into quaternary petalled self-assemblies at an intracellular acidic pH of 5.0. The quaternary petalled self-assemblies lead to a mechanical disruption effect on lysosomes like nanomachines, further resulting in enhanced drug delivery efficiency of an anticancer drug-loaded multicyclic copolymers with a tumor inhibition rate 1.6-fold greater than that of the free drug in a murine 4T1 model. Overall, our work highlights the use of HMCs as biomimetic allostery of SPSAs for enhanced biomedical applications. Synthetic polymer self-assemblies enable bio-inspired soft materials but are limited by structural complexity and poor stability. Here, the authors report topological polymers with hydrophilic multicycles that form stable nanoparticles, transform at acidic pH into quaternary structures, and enhance anticancer drug delivery with 1.6-fold higher tumor inhibition.