Mitochondrial Rapid Accumulation and Self-Enhanced Penetrating Nanomedicine for Tumor Multi-role Treatment

The inherent tumor microenvironment of solid tumors greatly limits the deep tissue delivery of drug agents and thus faces an unprecedented therapeutic dilemma. Herein, a potentially valuable strategy was developed based on a nonionic surfactant (HS) through a co-assembly technique to realize the loading, rapid cellular uptake/mitochondrial targeting, and penetrating application of the hydrophobic anticancer drug (IR780). This modular platform co-assembles diverse hydrophobic drugs, demonstrating broad applicability. Different from the way of traditional nanomedicine action, the obtained nanomedicine (IR780@HS) enters cells through clathrin-mediated and lipid raft-mediated endocytosis instantly, and then rapidly accumulates to mitochondria, therefrom exerting a synergistic antitumor effect. Furthermore, it could escape from dying tumor cells to other alive tumor cells to achieve effective penetration of three-dimensional tumor spheroids and orthotopic tumor models to avoid liver retention. IR780@HS thus overcomes key microenvironmental and pharmacokinetic obstacles, offering potential applications in the multi-role treatment of solid tumors in the future.