Vicious-cycle-breaking antiangiogenic nano-delivery systems potentiate and simplify the tumor vascular normalization strategy.

The theory of tumor vascular normalization provides new possibilities for the rational use of anti-angiogenesis drugs and chemotherapeutics. However, clinical implementation of vascular normalization strategies faces two key bottlenecks: figuring out the right dosage of anti-angiogenic agents to balance angiogenic and anti-angiogenic properties, and the technical challenge of real-time monitoring of transient normalization windows for best therapeutic timing. Additionally, tumor-associated macrophages (TAMs) often antagonize this therapy by interacting with tumor vasculature. In response to these challenges, in this study, anlotinib (ANB) was chosen as the model drug, and two drug delivery systems loaded with ANB were prepared and compared: sialic acid-cholesterol conjugate-modified liposomes (ANB-SL) and polysialic acid-modified electrostatic complexes (ANB-PSA). The results showed that ANB-SL specifically targets TAMs, then enriches within the tumor, releases ANB, killing TAMs while inhibiting vascular endothelial cells, thereby achieving tumor vascular normalization. This promotes CD8+ T cell infiltration, shifts the immunosuppressive tumor microenvironment (TME) to an immune-activated state, and enhances drug delivery efficiency. Meanwhile, ANB that reaches the interior of the tumor can inhibit the proliferation of tumor cells. This means that ANB-SL can subsequently exert its anti-tumor cytotoxic effect after restoring vascular normalization, without the need to determine the precise timing of the normalization window. Accordingly, ANB-SL is expected to potentiate and simplify the tumor vascular normalization strategy, providing new insights for cancer treatment.