Ultrasonic Cavitation‐Manipulated Macrophages Hitchhiking Augments Delivery of Nanocarriers for Active and Efficient Cancer Therapy

Abstract Cell‐derived vehicles have shown promise in drug delivery for cancer therapy, but they are hindered by lack of effective methods to release drug from cellular vehicles. To overcome this dilemma, this work develops nanodrug‐hitchhiking macrophages (OGNLN@MACs) that can unload drugs under ultrasound irradiation. The OGNLN is perfluoropentane‐loaded liposomal nanodroplet which consists of lipophilic prodrugs of elaidate‐conjugated gemcitabine and NLG919. OGNLN is internalized into macrophages to form OGNLN@MACs. OGNLN@MACs maintain the ability of tumor‐tropic migration as macrophages, and infiltrate solid tumors after intravenous injection. Subsequent local ultrasound irradiation induces liquid‐gas phase transition of perfluoropentane and ultrasonic cavitation, which causes OGNLN@MACs to rupture and release nanodrugs at tumor sites. The nanodrugs penetrate tumor parenchyma and exhibit potent antitumor activity via chemo‐immunotherapy. This study presents a promising strategy for efficient cancer therapy by utilizing ultrasound‐regulated nanodrug‐hitchhiking macrophages.