School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, 230027, P.R. China.
Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China.
Adv Drug Deliv Rev. 2017 Jun 1;115:98-114. doi: 10.1016/j.addr.2017.03.004. Epub 2017 Apr 7.
Cascades of systemic and intracellular obstacles, including low stability in blood, little tumor accumulation, weak tumor penetration, poor cellular uptake, inefficient endosomal escape and deficient disassembly in the cytoplasm, must be overcome in order to deliver nucleic acid drugs for cancer therapy. Nanocarriers that are sensitive to a variety of physiological stimuli, such as pH, redox status, and cell enzymes, are substantially changing the landscape of nucleic acid drug delivery by helping to overcome cascaded systemic and intracellular barriers. This review discusses nucleic acid-based therapeutics, systemic and intracellular barriers to efficient nucleic acid delivery, and nanocarriers responsive to extracellular and intracellular biological stimuli to overcome individual barriers. In particular, responsive nanocarriers for the cascaded delivery of nucleic acids in vivo are highlighted. Developing novel cascaded nanocarriers that transform their physicochemical properties in response to various stimuli in a timely and spatially controlled manner for nucleic acid drug delivery holds great potential for translating the promise of nucleic acid drugs and achieving clinically successful cancer therapy.
为了将核酸药物用于癌症治疗，必须克服包括血液中稳定性低、肿瘤积累少、肿瘤穿透性弱、细胞摄取效率低、内涵体逃逸效率低以及细胞质中缺乏有效解体等在内的一系列系统性和细胞内障碍。对各种生理刺激（如 pH 值、氧化还原状态和细胞酶）敏感的纳米载体正在通过帮助克服系统性和细胞内障碍，从根本上改变核酸药物递送的格局。本文综述了基于核酸的治疗方法、高效核酸递送的系统性和细胞内障碍，以及对外界和细胞内生物刺激有响应的纳米载体来克服各个障碍。特别强调了用于体内核酸级联递送的响应性纳米载体。开发新型级联纳米载体，使其在体内及时和空间控制的方式下响应各种刺激，改变其理化性质，用于核酸药物递送，为转化核酸药物的前景和实现癌症治疗的临床成功提供了巨大的潜力。
