PSMA‐Targeting Macrophage Membrane‐Coated Nanoparticles for Precision Diagnosis and Combination Therapy of Prostate Cancer

ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer in males. Advanced PCa is invasive and may spread rapidly. Current strategies could not fulfill the requirement for clinical application; thus, novel therapeutic strategies are still urgently needed. Nanoparticles are a promising strategy for targeted drug delivery and cancer treatment; however, the strong exogeneity and weak targeting limit their further application. Here, we developed a novel macrophage membrane‐coated nanoparticle that has transmembrane‐expressed gy‐1, a single‐chain antibody fragment (scFv) against prostate‐specific membrane antigen (PSMA), to endow the immune evasion and targeting property, which we named P‐MMCNPs. The Fe 3 O 4 @Au nanoparticles were used as the core of P‐MMCNPs, which confer P‐MMCNPs with the properties of multimodal imaging and photothermal therapy (PTT). Anti‐tumor cytotoxic drug maytansine (DM1) was loaded into the nanoparticles to obtain cytotoxicity. P‐MMCNPs were shown to have immune evasion capacity and prolonged circulation time and can be specifically distributed in PSMA‐positive tumors, thus enabling targeted imaging and targeted drug delivery. The macrophage membrane‐coated nanoparticles combined to inhibit tumor growth in vivo when loaded with DM1 and treated with PTT. Additionally, we found that P‐MMCNPs alone could inhibit tumor growth, which may be caused by cytokine neutralization by the macrophage membrane. Our work demonstrates that the innovative P‐MMCNPs serve as a versatile platform. This platform improves PCa‐targeted diagnostic and therapeutic efficacy while avoiding side effects. Moreover, it holds promise for expanding into the diagnosis and treatment of other diseases, with potential for clinical translation. Additionally, it offers novel insights into nanomedicine‐based combination therapy.