Chang Xin, Liu Chang, Han Yu-Mo, Li Qiu-Ling, Guo Bin, Jiang Hu-Lin
School of Pharmacy, Jinzhou Medical University, Jinzhou, Liaoning 121001, China.
Liaoning Provincial Key Laboratory of Marine Bioactive Substances, Jinzhou Medical University, Jinzhou, Liaoning 121001, China.
Mol Ther Nucleic Acids. 2023 Apr 11;32:415-431. doi: 10.1016/j.omtn.2023.04.006. eCollection 2023 Jun 13.
Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.
肺纤维化（PF）是一种病理机制复杂的间质性肺疾病，目前缺乏能够完全治愈它的治疗方法。将基因治疗与药物联用为协同逆转PF提供了有前景的治疗策略。然而，提高治疗性核酸的细胞内积累和转染效率仍然是一个迫切需要解决的关键问题。在此，我们开发了一种具有高转染效率的脂质纳米颗粒（PEDPs），其共负载核因子红细胞2相关因子2的pDNA（pNrf2）和吡非尼酮（PFD）用于PF治疗。PEDPs能够穿透生物屏障，在靶部位积累并发挥治疗作用，最终通过Nrf2与PFD的协同作用减轻II型肺泡上皮细胞（AECs II）中的氧化应激失衡，并抑制肌成纤维细胞过度活化，从而逆转PF。此外，我们系统地设计了各种脂质体（LNPs），证明降低聚乙二醇（PEG）比例可显著提高LNPs的摄取和转染效率，并提出了这种影响的可能机制。本研究清楚地表明，控制PEDPs中PEG的组成比例能够有效地将治疗药物递送至AECs II，提高pNrf2转染效率，并与PFD协同作用，以前瞻性策略逆转PF。
