Lu Zheng-Rong, Sun Da
Department of Biomedical Engineering, Case Western Reserve University, Wickenden Building, Room 427, 10900 Euclid Avenue, Cleveland, OH, 44106-7207, USA.
Pharm Res. 2025 Jul 8. doi: 10.1007/s11095-025-03890-8.
Lipid nanoparticles (LNPs) are among the most successful classes of nonviral delivery systems for nucleic acid-based therapeutics in treating human diseases. One of the key challenges in achieving efficient cytosolic delivery of nucleic acids is overcoming endosomal entrapment within cells. Conventional lipid bilayer-forming cationic and amino lipids mediate endosomal escape via the mechanism of lamellar-to-inverted hexagonal phase transition, resulting in suboptimal cytosolic cargo delivery. pH-sensitive amphiphilic cell membrane disruption and endosomal escape have emerged as a strategy for designing protonatable or ionizable lipids, especially nonlamellar lipids, for efficient cytosolic nucleic acid delivery. Nonlamellar amino lipids possess a large wedge-shaped tail structure and do not form stable lipid bilayers. These lipids and their corresponding LNPs remain neutral, non-amphiphilic, or minimally amphiphilic at physiological pH (7.4). They become amphiphilic upon protonation or ionization in acidic endosomes (pH 6.5-5.4). The electrostatic interaction of ionized nonlamellar lipids with the negatively charged endosome membrane, combined with their large wedge-like structures, disrupts the lipid bilayer, facilitating efficient endosomal escape. Additionally, the nonlamellar ionizable lipids can be fine-tuned by altering the structure of amino head groups and lipid tails to achieve the precisely controlled pH-sensitive amphiphilic membrane disruption at endosomal pH. Therefore, these lipids exhibit excellent safety profiles and high efficiency for in vivo delivery of various therapeutic nucleic acids. pH-sensitive amphiphilic membrane disruption and endosomal escape provide a feasible and effective mechanism for designing ionizable lipids for safe and efficient in vivo nucleic acid delivery.
脂质纳米颗粒（LNPs）是用于基于核酸的治疗药物治疗人类疾病的最成功的非病毒递送系统类别之一。实现核酸有效胞质递送的关键挑战之一是克服细胞内的内体截留。传统的形成脂质双层的阳离子脂质和氨基脂质通过层状到反相六方相转变的机制介导内体逃逸，导致胞质货物递送效果欠佳。pH敏感的两亲性细胞膜破坏和内体逃逸已成为设计可质子化或可离子化脂质（特别是非层状脂质）以实现高效胞质核酸递送的一种策略。非层状氨基脂质具有大的楔形尾部结构，不会形成稳定的脂质双层。这些脂质及其相应的LNPs在生理pH值（7.4）下保持中性、非两亲性或极低的两亲性。它们在酸性内体（pH 6.5 - 5.4）中质子化或离子化后变为两亲性。离子化的非层状脂质与带负电荷的内体膜的静电相互作用，结合其大的楔形结构，破坏脂质双层，促进有效的内体逃逸。此外，非层状可离子化脂质可以通过改变氨基头部基团和脂质尾部的结构进行微调，以在内体pH值下实现精确控制的pH敏感两亲性膜破坏。因此，这些脂质在体内递送各种治疗性核酸时表现出优异的安全性和高效率。pH敏感的两亲性膜破坏和内体逃逸为设计可离子化脂质以实现安全高效的体内核酸递送提供了一种可行且有效的机制。
