Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy
Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy
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DOI：
10.1073/pnas.1502281112
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发表时间：
2015-07-14
影响因子：
11.1
通讯作者：
Suk, Jung Soo
中科院分区：
文献类型：
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作者：
Mastorakos, Panagiotis;da Silva, Adriana L.;Suk, Jung Soo
基因治疗已成为治疗传统疗法难治性疾病的替代方案。基于合成纳米颗粒的基因递送系统为治疗基因的递送提供了高度可调的平台。然而，不能实现持续的，高水平的转基因表达在体内提出了一个重大的障碍。呼吸系统，虽然容易接近，仍然是一个具有挑战性的目标，因为有效的基因治疗要求在生理液体中的胶体稳定性和克服在肺中发现的生物屏障的能力。我们基于最先进的可生物降解聚合物聚（β-氨基酯）（PBAE）配制了高度稳定的DNA纳米颗粒，具有聚乙二醇的致密冠。我们发现，这些纳米颗粒有效地穿透了纳米多孔和高粘性的人粘液凝胶层，该层构成了到达下层上皮的主要屏障。我们还发现，这些PBAE为基础的粘液穿透DNA纳米粒子（PBAE-MPP）提供了均匀和高水平的转基因表达在整个小鼠肺，上级优于几个金标准的基因传递系统。PBAE-MPP在单次给药后至少4个月内实现了稳健的转基因表达，并且其转染效率不会因重复给药而减弱，这强调了其临床相关性。重要的是，PBAE-MPP表现出良好的安全性，在腹膜内给药后没有毒性迹象。
Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(beta-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.