SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics by pancreatic cancer cells

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future. CLip@siATG5 sequentially overcomes multiple barriers and effectively delivers siATG5 to pancreatic cancer cells. Then, cancer cells are pushed to transfer from autophagy to macropinocytosis, swallowing massive cytotoxic albumin-bound chemotherapeutics (Nab-PTX). [Display omitted] •Cancer cell membrane camouflage enabled the CLip@siATG5 to evade the MPS uptake and be preferentially taken up by the homotypic cancer cells.•Calcium phosphate (CaP) core dissolution in acid endosomes promoted siATG5 release in the cytoplasm.•CLip@siATG5 could deliver a sufficient concentration of siATG5 to in vivo pancreatic cancer cells for autophagy inhibition.•CLip@siATG5 pushed pancreatic cancer cells to transfer from autophagy to macropinocytosis and take up massive Nab-PTX.