Photo‐Empowered Macrophage‐Based Drug Delivery System Overcomes Motility Suppression and Significantly Enhances Deep Tumor Drug Delivery

Abstract Recently, cell‐based drug delivery systems emerge as highly promising alternatives in the field of antitumor therapy. These systems are characterized by their excellent biocompatibility, robust drug‐loading capacity, and the ability to effectively traverse biological barriers. However, the immunosuppressive tumor microenvironment significantly weakens the motility of immune cells, which is crucial for efficient drug delivery. A novel photo‐empowered macrophage‐based (PEM) drug delivery system is successfully developed in this study. The system is modified with thylakoids extracted from spinach leaves. Upon stimulation with light of specific wavelengths, the thylakoids generate ATP through photochemical reactions, thereby significantly enhancing the motility of macrophages and effectively overcoming the limitations imposed by the tumor microenvironment. In this work, the PEM system is loaded with two antitumor drugs: doxorubicin (Dox) and tirapazamine (TPZ). The results demonstrate that the system not only significantly improves the delivery efficiency of drugs to deep tumor tissues but also greatly enhances antitumor therapeutic efficacy. Particularly after deep infiltration into tumor tissues, the PEM system efficiently eradicates hypoxic and drug‐resistant tumor cells, showcasing remarkable performance. This innovative PEM strategy provides a new approach for deep tumor drug delivery and addressing multidrug resistance, holding great promise for a significant breakthrough in antitumor therapy.