Exploiting eNOS activation to achieve tumor vascular normalization via endothelial transcytosis of lipid nanoparticles

Abnormal tumor vasculature greatly accelerates tumor progression and diminishes antitumor treatments. Restoring perivascular NO gradients is available to maintain tumor vessel homeostasis and promote tumor vascular normalization. However, exogenously delivering NO strategies lacks the durability to maintain precise NO localization around tumor vessels. Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO2 into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies. The Ca2+ and Met released in ECs could restore perivascular localization of NO by activating endothelial NOS (eNOS). Additionally, MC@L internalized by tumor cells could cause CaO2-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O2 generation and H+ consumption during CaO2 degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.