Supramolecular Polymer‐Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage‐Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti‐Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma

Anti‐angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro‐angiogenic factors in the tumor microenvironment (TME) in response to anti‐angiogenic therapy, recruiting tumor‐associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti‐angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX‐PMI) co‐assembled by anti‐angiogenic nanomedicines (PCN‐Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs‐reprogramming polyTLR7/8a nanoregulators (p(Man‐IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN‐Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man‐IMDQ) NRs repolarize pro‐angiogenic M2‐type TAMs into anti‐angiogenic M1‐type TAMs via mannose‐binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1‐6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2‐subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti‐angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system‐based synergistic approach for tumor therapy.