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RNA疗法在代谢性疾病治疗中的运用
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Abstract:
代谢性疾病涉及多器官、多通路病理网络，现有药物治疗常需长期联合用药，且长期疗效与耐受性仍受限制。本文围绕RNA疗法在代谢性疾病中的研究进展，系统梳理小干扰RNA (siRNA)、反义寡核苷酸(ASO)、微小RNA (miRNA)及短发夹RNA (shRNA)的作用机制与技术特点，总结GalNAc偶联、脂质纳米颗粒(LNP)等主流递送平台的适用范围，并分别总结肥胖、2型糖尿病、MASLD/MASH和高脂血症的主要干预靶点及转化现状。综合分析表明，高脂血症因靶点集中且肝递送路径成熟转化程度较高；MASLD/MASH与肝靶向平台适配性强，具备较明确的推进基础；肥胖与糖尿病由于多组织参与，RNA疗法更适用于关键节点干预及联合策略。总体而言，递送效率、组织选择性与长期安全性仍是限制拓展适应症的主要问题。
Metabolic diseases involve complex multi-organ and multi-pathway pathological networks, and current pharmacological treatments often rely on long-term combination therapies with limitations in sustained efficacy and tolerability. This review summarizes recent advances in RNA therapeutics for metabolic diseases, systematically outlining the mechanisms and technical features of small interfering RNA (siRNA), antisense oligonucleotides (ASOs), microRNAs (miRNAs), and short hairpin RNA (shRNA). Major delivery platforms, including GalNAc conjugation and lipid nanoparticles (LNPs), are discussed with respect to their applicability and translational potential. In addition, key therapeutic targets and current progress are reviewed across obesity, type 2 diabetes mellitus, MASLD/MASH, and hyperlipidemia. Comparative analysis indicates that RNA-based therapies for hyperlipidemia have achieved the highest level of clinical translation due to well-defined targets and mature liver-directed delivery strategies. MASLD/MASH shows strong compatibility with hepatic targeting platforms and holds substantial translational promise, whereas obesity and type 2 diabetes involve multi-tissue regulation, making RNA therapeutics more suitable for intervention at critical regulatory nodes or as part of combination therapies. Overall, delivery efficiency, tissue selectivity, and long-term safety remain the major challenges limiting the expansion of RNA therapeutics to broader metabolic indications.
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