A hyaluronic acid nanogels based exosome production factory for tumor photothermal therapy and angiogenesis inhibition

Exosomes as a unique drug delivery system provide a new choice for tumor therapy. However, the in vitro functionalization of exosomes and the process of circulating drug delivery can easily cause exosome degradation and drug loss, thus reducing the efficiency of drug delivery. In this work, based on the endocyto-fusion-exocytosis pathway of exosome formation, a multifunctional hyaluronic acid nanogel loaded with the antiangiogenic drug vatalanib and the near-infrared photothermal agent indocyanine green (ICG) was designed. Lysosome escape and photothermal therapy were combined to promote exosome production. Hyaluronic acid nanogels were endocytosed by tumor cells with CD44 mediation, forming intracellular vesicle-coated nanogels, which were subsequently degraded by hyaluronidase with high expression in tumor cells. Anti-angiogenic signals in intracellular vesicles were then delivered to vascular endothelial cells by exosomes through membrane fusion and exocytosis, which inhibited tumor angiogenesis to prevent tumor proliferation and metastasis. Cell experiments and tumor models demonstrate that our therapeutic strategy can achieve effective tumor inhibition.