Pulmonary fibrosis (PF) is a progressive chronic disease characterized by a continuous decline in lung function, for which effective therapies remain elusive. Increasing evidence suggests that the recruitment of fibrocytes from the circulatory system to lungs plays a pivotal role in the pathogenesis of PF. Once into the lungs, these fibrocytes differentiate into myofibroblasts, the primary producers of extracellular collagen. Given the difficulty in reversing the disease course, targeting this key mechanism in the early stages of the disease presents a promising therapeutic strategy. To this end, we engineered a plerixafor (CXCR4 antagonist)-modified serum albumin delivery system loaded with a cisplatin prodrug (Cpro@P-SA). This system is specifically designed to target CXCR4-positive circulating fibrocytes after intravenous administration, enhance cellular uptake of Cpro@P-SA, and facilitate the intracellular conversion of cisplatin prodrug to exert its cytotoxic effects, thereby inducing fibrocytes apoptosis. Utilizing a bleomycin-induced PF mouse model, we have demonstrated that Cpro@P-SA maintains prolonged circulation, enabling it to selectively identify and eradicate recruiting fibrocytes with an optimized treatment regimen. Our results confirm that Cpro@P-SA can effectively reduce fibrocyte levels in the circulatory system, thereby mitigating PF symptoms and controlling disease progression, as evidenced by key biochemical markers and histological analyses. Furthermore, the safety of this designed system was validated through multiple evaluations. Consequently, Cpro@P-SA offers a novel and promising therapeutic approach for the treatment of early PF.
Keywords: Albumin nanoparticles; CXCR4; Cisplatin; Fibrocyte; Pulmonary fibrosis.
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