Iversen Alexandra, Utterström Johanna, Das Basab Kanti, Selegård Robert, Khare Lalit Pramod, Aili Daniel
Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Linköping University, 581 83 Linköping, Sweden.
J Mater Chem B. 2025 Jul 31. doi: 10.1039/d5tb00304k.
Liposomes are widely utilized in drug delivery systems to enhance pharmacokinetics and reduce side effects. Bioresponsive membrane-active peptides (MAPs) can modulate the release of encapsulated drugs from liposomes, improving therapeutic efficacy. However, achieving efficient and specific conjugation of MAPs to liposomes remains challenging, complicating translational efforts. Thiol-maleimide Michael addition is an attractive strategy for lipid conjugation of cysteine-containing MAPs but is hindered by thiol oxidation. Strain-promoted azide-alkyne cycloaddition (SPAAC) presents an alternative conjugation approach, yet its effects on liposome and peptide functionality are not fully understood. Here, we demonstrate how these two conjugation strategies influence peptide-liposome interactions and lipid membrane permeability using a designed bioresponsive MAP. Both strategies result in MAP accumulation on liposomes, but their effects on membrane integrity and release dynamics differ significantly. SPAAC-based conjugation is generally much slower than the corresponding thiol-maleimide reaction. The inclusion of cholesterol in liposomes has a pronounced impact on both conjugation reactions, leading to phase separation and unexpected cross-reactivity. Accounting for these effects enabled orthogonal MAP-liposome functionalization and selective, sequential release from mixed liposome populations using different MAPs. These findings highlight the critical role of conjugation chemistry and lipid composition in designing MAP-based bioresponsive liposomal drug delivery systems. Understanding these interactions allows for the fine-tuning of liposomal formulations to optimize drug release, opening new avenues for enhancing the efficacy of liposomal therapeutics.
脂质体被广泛应用于药物递送系统，以增强药代动力学并减少副作用。生物响应性膜活性肽（MAPs）可以调节脂质体中包封药物的释放，提高治疗效果。然而，实现MAPs与脂质体的高效、特异性偶联仍然具有挑战性，这使得转化研究变得复杂。硫醇-马来酰亚胺迈克尔加成反应是一种用于含半胱氨酸MAPs脂质偶联的有吸引力的策略，但受到硫醇氧化的阻碍。应变促进叠氮化物-炔烃环加成反应（SPAAC）提供了一种替代的偶联方法，但其对脂质体和肽功能的影响尚未完全了解。在这里，我们使用一种设计的生物响应性MAP展示了这两种偶联策略如何影响肽-脂质体相互作用和脂质膜通透性。两种策略都导致MAPs在脂质体上积累，但它们对膜完整性和释放动力学的影响有显著差异。基于SPAAC的偶联通常比相应的硫醇-马来酰亚胺反应慢得多。脂质体中胆固醇的加入对两种偶联反应都有显著影响，导致相分离和意外的交叉反应。考虑到这些影响，能够实现正交的MAP-脂质体功能化，并使用不同的MAPs从混合脂质体群体中进行选择性、顺序释放。这些发现突出了偶联化学和脂质组成在设计基于MAP的生物响应性脂质体药物递送系统中的关键作用。了解这些相互作用有助于对脂质体制剂进行微调以优化药物释放，为提高脂质体治疗效果开辟了新途径。
