Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment

Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Möbius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency. FLG nanodrugs inducing vascular normalization and MAR/MPA nanodrugs blocking CCL5/CCR5 pathway are prepared to construct mutually reinforcing crosstalk between vascular normalization and tumor microenvironment [Display omitted] •FLG nanodrugs preferentially accumulated in vascular endothelial cells.•In acid condition, GA prototype was released through quinone methyl rearrangement.•FLG nanodrugs induced vasculature normalization of 5 days.•CCL5/CCR5 pathway blocker extended vasculature normalization window to 9 days.•A mutual reinforcing loop was constructed by vascular repairing and TME regulation.