Biomimetic nanodrug breaching tumor cell membrane barrier for high-efficiency drug delivery

The inefficient delivery of drugs into tumor cells by nanodrugs remains a major challenge in enhancing drug utilization. Herein, inspired by the mechanism used by cytotoxic T lymphocytes (CTL) to efficiently deliver granzyme into tumor cells by recognizing tumor cells, damaging membranes and facilitating drug entry into cells, the biomimetic nanodrug (Mem-Poly/CaO 2 /Dox) was developed. This nanodrug utilized acid and ATP dual responsiveness to perforate tumor cell membrane and enhance directly intracellular drug delivery. Upon administration, Mem-Poly/CaO 2 /Dox recognized homologous tumor cells through its surface-coated tumor cell membrane. Then, Mem-Poly/CaO 2 /Dox responded to acidic tumor environment and rapidly released calcium peroxide nanoparticles (CaO 2 ). The released CaO 2 adhered to the tumor cell membrane and subsequently generated hydrogen peroxide (H 2 O 2 ) in situ within acidic tumor microenvironment, causing membrane injured and forming micro holes. This membrane disruption led to ATP leakage from tumor cells, further triggering the disassembly of the responsive polymer and Dox release. The released Dox then directly entered tumor cells through the damaged membrane and induced cell death through apoptosis and ferroptosis. Experimental results demonstrated that Mem-Poly/CaO 2 /Dox achieved significantly higher drug delivery efficiency than conventional nanodrugs, which primarily rely on the endocytosis-lysosomal escape pathway. By simulating the granzyme delivery mechanism of CTL, this highly efficient strategy breaches biological barriers of the cell membrane and offers a promising strategy to improve delivery efficiency and anti-tumor potency of chemotherapeutics.