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.

有害的肿瘤微环境 (TME) 依赖于扭曲的肿瘤血管系统来进一步扩大肿瘤。血管正常化疗法通过血管修复部分改善了 TME，而这些疗法由于每次尝试都受到来自 TME 的促血管生成因子的阻碍，从而进入一个牢不可破的莫比乌斯环，导致血管正常化的持续时间和程度有限。在这里，我们开发了一个包含 FLG 和 MAR/MPA 纳米药物的纳米系统来调节肿瘤血管系统和 TME。FLG纳米药物是通过将VEGF/VEGFR2抑制性低分子量肝素和藤黄酸与F3肽修饰连接而构建的，用于直接调节血管内皮细胞并诱导血管正常化。同时，包裹 CCL5/CCR5 阻滞剂 maraviroc 的 MAR/MPA 纳米药物旨在限制血管生成和 TME 恶化的细胞因子功能，有助于血管系统修复和 TME 重建。我们的结果表明，这种组合纳米系统协同诱导持续 9 天的血管正常化窗口，并恢复了 Panc-1 肿瘤的血管通透性和氧供应。此外，在黑色素瘤中，我们的纳米系统通过增加 CD4 的浸润实现了免疫改善⁺和 CD8 ⁺ T 细胞在改造的 TME 中。这两种纳米药物在血管修复和 TME 改善方面相互帮助，成功地将恶性串扰逆转为积极的串扰，实现了整体 TME 重塑并提高了治疗效率。