工程化外泌体在肺纤维化靶向治疗中的研究进展

Research Progress on Engineered Exosomes in Targeted Therapy for Pulmonary Fibrosis

摘要: 肺纤维化(pulmonary fibrosis, PF)是慢性肺病发展的严重阶段，其特征是肺间质内细胞外基质的过度沉积与组织结构破坏，最终导致呼吸衰竭。而现有抗纤维化药物仅能延缓病程、无法逆转纤维化且副作用明显。外泌体是细胞分泌的脂质纳米囊泡，具有良好的生物相容性、低免疫原性和穿透生物屏障的能力，但天然外泌体存在靶向性不足、载药效率低、规模化制备困难等局限，限制了其临床转化。工程化外泌体通过靶向修饰、药物负载优化及功能化改造，为实现更精准、更高效、更安全的抗纤维化治疗提供了新策略。通过靶向修饰，优化药物负载技术及功能改造，提升了外泌体应用的精准性、效能与安全性，推动外泌体疗法从“概念验证”迈向“精准干预”。本文系统梳理了PF的病理机制与关键治疗靶点，重点归纳了工程化外泌体的构建策略、作用机制、临床前应用与协同增效效应，并分析了当前面临的标准化生产、质量控制与长期安全性等挑战，展望了合成生物学与人工智能驱动的智能外泌体发展方向，旨在为PF的精准治疗提供理论参考与技术支持。

Abstract: Pulmonary fibrosis (PF) is a severe stage in the progression of chronic lung diseases, characterized by excessive deposition of extracellular matrix within the pulmonary interstitium and destruction of tissue architecture, ultimately leading to respiratory failure. However, currently available antifibrotic drugs can only slow disease progression, fail to reverse established fibrosis, and are associated with notable side effects. Exosomes are lipid nanovesicles secreted by cells that possess good biocompatibility, low immunogenicity, and the ability to penetrate biological barriers; nevertheless, natural exosomes suffer from limitations such as insufficient targeting, low drug-loading efficiency, and difficulties in large-scale production, which restrict their clinical translation. Through targeted modification, optimized drug loading, and functionalization, engineered exosomes offer a new strategy for achieving more precise, more efficient, and safer antifibrotic therapy, providing a viable path to overcome the aforementioned challenges. Their core value lies in enhancing the precision, efficacy, and safety of treatment, thereby advancing exosome therapy from “proof of concept” toward “precise intervention”. This review systematically outlines the pathological mechanisms and key therapeutic targets of PF, focuses on summarizing the construction strategies, mechanisms of action, preclinical applications, and synergistic effects of engineered exosomes, and analyzes the current challenges in standardized production, quality control, and long-term safety. It further looks ahead to the development of intelligent exosomes driven by synthetic biology and artificial intelligence, aiming to provide theoretical reference and technical support for the precise treatment of PF.