A Dual Drug‐Loaded Smart Liposome System Capable of Capturing Leukemia Cells Followed by Releasing Drugs Within Cells for Synergistic Therapy

Abstract Acute Promyelocytic Leukemia (APL) is commonly treated with a combination of arsenic and all‐trans retinoic acid (RA). However, the co‐administration of two different preparations results in pharmacokinetic inconsistencies and serious side effects, compromising their efficacy. Liposomes provide a promising alternative for co‐delivery. In this study, cholesterol‐free corosolic acid (CA) liposome is designed as a functional carrier, loading arsenic precipitation and a RA derivative (RAD) at a synergy ratio. The dual drug‐loaded CA liposome (CALP) is further modified with a T7 peptide (T‐CALP) to target the overexpressed CD71 on APL cells. T‐CALP in the bloodstream bypasses blood cells and specifically recognizes APL cells, facilitating efficient internalization via CD71‐mediated endocytosis and CALP's unique membrane‐penetration capability. Arsenic and RAD can attain synergistic release within cells through acid‐responsive mechanism and membrane fusion respectively, resulting in a powerful effect by inducing apoptosis and differentiation of APL cells. In orthotopic APL mice model, blank liposomes are co‐administered to curtail the liver clearance of T‐CALP. This allows long‐circulating T‐CALP to effectively reduce leukemia cell numbers and nearly halt tissues infiltration. Notably, T‐CALP considerably extends the survival time of APL mice and achieves a curative effect, demonstrating its potential as a precision combination therapy for APL.