构象介导的聚氨基酸囊泡用于大分子药物递送

Conformation-Mediated Poly(amino acid) Vesicles for Macromolecular Drug Delivery

摘要

大分子药物因其高特异性、多功能性及良好的生物相容性而备受关注，但其稳定性差、跨膜能力不足等缺陷严重制约了临床转化。纳米药物载体虽可有效提高药物的生物利用度与靶向性，但如何实现大分子药物的高效胞内递送及可控释放，仍是该领域亟待攻克的核心难题。本研究设计并合成了具有不同构象的两亲性聚氨基酸，该类聚合物可自组装形成囊泡，用于高效包载亲水性大分子药物。研究表明，与具有β-折叠构象的聚氨基酸囊泡相比，具有α-螺旋构象的聚氨基酸囊泡因分子间作用力相对较弱，从而表现出更优异的膜通透性，有利于亲水性大分子药物的有效释放。尤为重要的是，α-螺旋构象增强了囊泡的膜活性，不仅能够促进肿瘤细胞对囊泡的高效摄取，还可有效介导其逃逸内吞-溶酶体途径，进而促进大分子药物在胞内的释放与分布。本研究为大分子药物的胞内递送提供了新策略，所构建的α-螺旋聚氨基酸囊泡作为一类新型纳米药物载体，展现出广阔的应用前景。

Abstract

Macromolecular drugs have attracted considerable attention owing to their high specificity, multifunctionality, and favorable biocompatibility. However, their clinical translation is severely hampered by inherent limitations, including poor stability and insufficient membrane-crossing ability. Although nanocarriers can improve the bioavailability and targeting of these drugs, achieving efficient intracellular delivery with controlled release remains a critical challenge. In this study, we design and synthesize amphiphilic poly(amino acid) derivatives with distinct conformations. These polymers self-assemble into polymersomes that efficiently encapsulate hydrophilic macromolecular drugs. Compared to their β-sheet counterparts, α-helical poly(amino acid) polymersomes exhibit relatively weaker intermolecular interactions, resulting in superior membrane permeability, thereby facilitating more effective release of the encapsulated cargo. Remarkably, the α-helical conformation also imparts enhanced membrane activity, which not only facilitates efficient uptake by tumor cells but also promotes endo-lysosomal escape, leading to improved intracellular release and distribution of macromolecular drugs. This study proposes a novel strategy for macromolecular drug delivery, and the engineeredα-helical poly(amino acid) polymersomes emerge as a promising category of nanocarriers with extensive translational application prospects.

关键词

聚氨基酸 / 构象 / 囊泡 / 药物递送 / 大分子药物

Key words

poly(amino acid) / conformation / vesicle / drug delivery / macromolecular drug

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基金资助

国家自然科学基金(52525305)

国家自然科学基金(52273140)

国家自然科学基金(52473313)

国家自然科学基金(52503189)

中国博士后科学基金(BX20240241)

中国博士后科学基金(2024M762213)