Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based nanomaterials have become widely used in the field of gene and drug delivery due to their structural versatility and biomimetic properties. Particularly, polypeptide gene vectors that respond to biological stimuli, such as acidic intracellular environments, have promising applications in mediating efficient endosomal escape and drug release. Unfortunately, synthesis strategies for efficient polymerization of acid-labile peptides have been limited due to conditions that fail to preserve acid-degradable functional groups. Stable urethane derivatives of the acid-labile amino acid ketalized serine (kSer) were synthesized and polymerized to a high molecular weight under permissive conditions independent of elevated temperature, restrictive solvents, or an inert atmosphere. A new formulation strategy utilizing solvent-driven self-assembly of poly(kSer) peptides with small interfering RNA (siRNA) was developed, and the resulting poly(kSer)/siRNA complexes were further cross-linked for reinforced stability under physiological conditions. The complexes were highly monodisperse and precisely spherical in morphology, which has significant clinical implications in definitive biodistribution, cellular internalization, and intracellular trafficking patterns. Self-assembled, cross-linked poly(kSer)/siRNA complexes demonstrated efficient nucleic acid encapsulation, internalization, endosomal escape, and acid-triggered cargo release, tackling multiple hurdles in siRNA delivery. The acid-responsive polypeptides and solvent-driven self-assembly strategies demonstrated in this study could be applicable to developing other efficient and safe delivery systems for gene and drug delivery.

中文翻译：

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溶剂驱动的自组装酸响应性聚缩酮丝氨酸/ siRNA复合物，可干扰RNA

生物纳米技术的进步旨在开发具有刺激响应功能的智能核酸传递载体，以克服诸如非生物降解性，快速清除，免疫反应和到达细胞内靶标等挑战。基于肽的纳米材料由于其结构的多功能性和仿生特性而已广泛用于基因和药物递送领域。特别地，对诸如酸性细胞内环境之类的生物刺激作出响应的多肽基因载体在介导有效的内体逃逸和药物释放中具有有希望的应用。不幸的是，由于不能保持酸可降解的官能团的条件，有效聚合酸不稳定肽的合成策略受到限制。合成了酸不稳定氨基酸缩酮化丝氨酸（kSer）的稳定氨基甲酸酯衍生物，并在不依赖于高温，限制性溶剂或惰性气氛的允许条件下聚合成高分子量。开发了一种利用溶剂驱动的具有小干扰RNA（siRNA）的聚（kSer）肽的自组装的新配制策略，并将所得的聚（kSer）/ siRNA复合物进一步交联以增强在生理条件下的稳定性。该复合物是高度单分散的并且在形态上精确地为球形，这在确定的生物分布，细胞内在化和细胞内运输模式中具有重要的临床意义。自组装，交联的poly（kSer）/ siRNA复合物证明了有效的核酸封装，内在化，内体逃逸和酸触发的货物释放，解决了siRNA传递中的多个障碍。这项研究中证明的酸反应性多肽和溶剂驱动的自组装策略可能适用于开发其他有效且安全的基因和药物递送系统。