FAP-activated liposomes achieved specific macropinocytosis uptake by pancreatic stellate cells for efficient desmoplasia reversal

The desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) severely compromises drug delivery and efficacy. To disrupt stromal barriers, we constructed an all-trans retinoic acid (ATRA)-loaded liposome, FrLip@R, that contained calcium phosphate (CaP) cores and arginine 12-mer peptide (r12) ligands shielded by fibroblast activation protein (FAP)-detachable polyglutamate. Shielding r12 protected FrLip@R from nonspecific uptake, e.g., eluding the mononuclear phagocyte system (MPS) uptake for extended blood retention. Then, FrLip@R could be specifically activated by FAP overexpressed on activated pancreatic stellate cells (PSCs) to expose r12, thereby promoting its PSC uptake via an efficient macropinocytosis pathway. Accordingly, FrLip@R exhibited 2.42- and 2.85-fold higher internalization by in vivo PSCs than r12-modified and unmodified liposomes, respectively. In particular, the FrLip amount in the FAP+ PSCs was 54.46-fold higher than that in the other intratumoral cells. In addition, CaP core dissolution in acidic endosomes promoted ATRA release in the cytoplasm. Through efficient and specific ATRA delivery, FrLip@R induced PSC quiescence and disrupted stromal barriers, enhancing intratumoral drug delivery. Finally, in a murine pancreatic cancer model, FrLip@R combined with gemcitabine exerted antitumor efficacy superior to a 1.5-fold dose of gemcitabine while avoiding its severe side effects. Furthermore, FrLip@R modulation created a microenvironment adverse to tumor growth. Therefore, FrLip@R represents a potent and safe stromal barrier-disrupting agent that can amplify chemotherapeutic efficacy in desmoplastic PDAC.