Enzyme‐Activated Prodrug‐Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

Abstract Tumor‐specific enhanced delivery of chemotherapeutics and modulators to tumor cells and activated pancreatic stellate cells (aPSCs), respectively, represents safer and more effective therapy for pancreatic cancer. Herein, a membrane type 1‐matrix metalloproteinase (MT1‐MMP)‐cleavable spacer is used to assemble low‐density cRGDfK onto thermosensitive liposomes loaded with phosphorylated calcipotriol (PCAL) and doxorubicin (DOX), yielding MR‐T‐PD. The liposome‐linked cRGDfK prodrug on MR‐T‐PD surface is first activated by MT1‐MMP, which is selectively expressed on tumor endothelial cells, to release cRGDfK. The free cRGDfK specifically promotes tumor angiogenesis, leading to 3.4‐fold higher accumulation and a wider distribution of MR‐T‐PD in tumors. Furthermore, MR‐T‐PD rapidly releases PCAL and DOX into the interstitium under heat treatment. The released DOX enters tumor cells to induce apoptosis, whereas the PCAL prodrug is converted to CAL by alkaline phosphatase on the surface of aPSCs; CAL can then enter aPSCs to induce quiescence and promote the antitumor effect of DOX. Finally, by enhancing the exposure of DOX and CAL to tumor cells and aPSCs, respectively, in a tumor‐specific manner, MR‐T‐PD exerts superior efficacy (a 5.9‐fold decrease in tumor weight) without causing additional side effects. Overall, this prodrug‐based smart liposome system represents a promising paradigm for pancreatic cancer therapy.