Catenacci Laura, Rossi Rachele, Sechi Francesca, Buonocore Daniela, Sorrenti Milena, Perteghella Sara, Peviani Marco, Bonferoni Maria Cristina
Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.
Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy.
Pharmaceutics. 2024 Nov 26;16(12):1521. doi: 10.3390/pharmaceutics16121521.
Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune system plays a critical role in the response to these nanocarriers, with innate immune cells initiating an early response and adaptive immune cells mediating a more specific reaction, sometimes leading to potential adverse effects. Recent studies have shown that the innate immune response to LNPs is mediated by Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs), which recognize the lipid components of the nanoparticles. This recognition can trigger the activation of inflammatory pathways and the production of cytokines and chemokines, leading to potential adverse effects such as fever, inflammation, and pain at the injection site. On the other hand, the adaptive immune response to LNPs appears to be primarily directed against the protein encoded by the mRNA cargo, with little evidence of an ongoing adaptive immune response to the components of the LNP itself. Understanding the relationship between LNPs and the immune system is critical for the development of safe and effective nucleic acid-based delivery systems. In fact, targeting the immune system is essential to develop effective vaccines, as well as therapies against cancer or infections. There is a lack of research in the literature that has systematically studied the factors that influence the interaction between LNPs and the immune system and further research is needed to better elucidate the mechanisms underlying the immune response to LNPs. In this review, we discuss LNPs' composition, physico-chemical properties, such as size, shape, and surface charge, and the protein corona formation which can affect the reactivity of the immune system, thus providing a guide for the research on new formulations that could gain a favorable efficacy/safety profile.
脂质纳米颗粒（LNPs）已显示出有望成为基于核酸的治疗药物的递送系统，包括DNA、小干扰RNA（siRNA）和mRNA疫苗。免疫系统在对这些纳米载体的反应中起关键作用，固有免疫细胞引发早期反应，适应性免疫细胞介导更特异性的反应，有时会导致潜在的不良反应。最近的研究表明，对LNPs的固有免疫反应由Toll样受体（TLRs）和其他模式识别受体（PRRs）介导，这些受体识别纳米颗粒的脂质成分。这种识别可触发炎症途径的激活以及细胞因子和趋化因子的产生，导致潜在的不良反应，如发热、炎症和注射部位疼痛。另一方面，对LNPs的适应性免疫反应似乎主要针对mRNA货物编码的蛋白质，几乎没有证据表明对LNP自身成分存在持续的适应性免疫反应。了解LNPs与免疫系统之间的关系对于开发安全有效的基于核酸的递送系统至关重要。事实上，针对免疫系统对于开发有效的疫苗以及针对癌症或感染的疗法至关重要。文献中缺乏系统研究影响LNPs与免疫系统相互作用因素的研究，需要进一步研究以更好地阐明对LNPs免疫反应的潜在机制。在本综述中，我们讨论了LNPs的组成、物理化学性质，如大小、形状和表面电荷，以及可影响免疫系统反应性的蛋白质冠形成，从而为可能获得良好疗效/安全性的新制剂研究提供指导。
