Synergistic Therapy of a Naturally Inspired Glycopolymer‐Based Biomimetic Nanomedicine Harnessing Tumor Genomic Instability

Abstract Inspired by natural saccharide‐protein complexes, a stimuli‐responsive biodegradable and branched glycopolymer–pyropheophorbide‐a (Ppa) conjugate (BSP) with saccharide units for cancer therapy is constructed. A linear glycopolymeric conjugate (LSP), a branched glycopolymeric conjugate (BShP) from Ppa with long carbon chains, and a branched conjugate (BHSP) based on poly[N‐(2‐hydroxypropyl) methacrylamide] (polyHPMA) without saccharide units are prepared as controls. Through structure–activity relationship studies, BSP with a 3D network structure forms stable nanostructures via weak intermolecular interactions, regulating the stacking state of Ppa to improve the singlet oxygen quantum yield and the corresponding photodynamic therapy (PDT) effect. BSP shows high loading of olaparib, and are further coated with tumor cell membranes, resulting in a biomimetic nanomedicine (CM‐BSPO). CM‐BSPO shows highly efficient tumor targeting and cellular internalization properties. The engulfment of CM‐BSPO accompanied with laser irradiation results in a prominent antitumor effect, evidenced by disruption of cell cycles in tumor cells, increased apoptosis and DNA damage, and subsequent inhibition of repair for damaged DNA. The mechanism for the synergistic effect from PDT and olaparib is unveiled at the genetic and protein level through transcriptome analysis. Overall, this biodegradable and branched glycopolymer–drug conjugate could be effectively optimized as a biomimetic nanomedicine for cancer therapy.