Abstract

An albumin-based nanosystem enables active gp60-mediated transvascular transport. • Synchronizing vascular normalization and stromal decompression reshapes PDAC TME. • Self-reinforced tumor accumulation arises from a perfusion-transcytosis loop. • Enhanced intratumoral drug infiltration leads to improved gemcitabine efficacy. The typical hypoperfused vasculature and desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) severely hinder the intratumoral perfusion and the outcomes of chemotherapeutics. Single vascular normalization ignores the physical compression on vessels restricting vascular remodeling extent, nor the tumoral diffusion obstacle established by the stroma. Worse still, it concurrently reduces vascular permeability for nanodrug. Stroma alleviation alone remains immature and disorganized vasculature, impeding hemoperfusion and drug transport. Here, we designed a permeable nanosystem with “self-propelling” ability, based on dodecyl-modified serum albumin (DSA), and utilized it to co-deliver genistein (Gen) and all-trans retinoic acid (ATRA) to sustainedly synchronize vascular normalization and matrix decompression in PDAC. Benefiting from DSA-gp60-based active transvascular transport, the nanodrug DSA/(Gen + ATRA) established a positive feedback loop between microenvironment reshaping and tumoral accumulation, mitigating the adverse impact of reduced vascular permeability. In vitro and in vivo data demonstrated that DSA/(Gen + ATRA) continuously increased the proportion of functional blood vessels alongside decreased stroma density, ultimately significantly enhancing the intratumoral infiltration and the antitumor potency of gemcitabine. This strategy proposes a paradigm for designing “self-propelled” nanoregulators for all-round microenvironment remodeling, offering a promising approach to improve the outcomes of PDAC chemotherapy. Download: Download high-res image (156KB) Download: Download full-size image