Optimizing Pluronic-PEI Nanocarriers for RNAi Delivery in Oral Cancer: From Polymer Synthesis to Functional Screening.

IF 5.4 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-10-06 DOI:10.1021/acs.biomac.5c01011

Cátia Domingues, Ivana Jarak, Jorge Coelho, Rui A Carvalho, Francisco Veiga, Carla Vitorino, Marília Dourado, Ana Figueiras

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引用次数: 0

Abstract

Oral squamous cell carcinoma (OSCC) treatment is hindered by the poor delivery of RNA interference (RNAi) therapeutics such as microRNAs (miRNAs). Here, we systematically explored the synthesis and functional optimization of Pluronic-polyethylenimine (PEI) nanocarriers for efficient miRNA delivery in OSCC. Among several Pluronic variants tested, only Pluronic L121 formed stable, fully cross-linked micellar nanogels via covalent bonding with low-molecular-weight PEI (1.8 kDa), enabling robust miRNA-100 complexation at an N/P ratio of 5:1. These cross-linked nanogels (PP03) outperform counterparts derived from other Pluronics or PEI alone, demonstrating enhanced cellular uptake and potent miRNA-mediated silencing in both 2D and 3D OSCC models. PP03 exploits a pH-sensitive ester linkage that facilitates endosomal escape through PEI's proton sponge effect combined with Pluronic-mediated osmotic modulation. The nanogels' rough 3D morphology confers superior colloidal stability and mucoadhesion, supporting oromucosal delivery. Furthermore, PP03 displayed hemocompatibility with no hemolytic or hemorrhagic events observed, highlighting its versatility for intravenous administration. This work emphasized the significance of polymer chemistry and cross-linking efficiency in designing functional RNAi nanocarriers, thereby advancing miRNA-based therapeutics for oral cancer.

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优化用于口腔癌RNAi递送的Pluronic-PEI纳米载体：从聚合物合成到功能筛选。

口腔鳞状细胞癌（OSCC）的治疗受到RNA干扰（RNAi）疗法如microRNAs （miRNAs）递送不良的阻碍。在此，我们系统地探索了pluronic -聚乙烯亚胺（PEI）纳米载体的合成和功能优化，以实现OSCC中miRNA的高效递送。在测试的几个Pluronic变体中，只有Pluronic L121通过与低分子量PEI （1.8 kDa）的共价键形成稳定的、完全交联的胶束纳米凝胶，以5:1的N/P比实现miRNA-100的稳定络合。这些交联纳米凝胶（PP03）在2D和3D OSCC模型中表现出增强的细胞摄取和有效的mirna介导的沉默，优于其他Pluronics或PEI单独衍生的同类产品。PP03利用ph敏感的酯链，通过PEI的质子海绵效应结合pluronic介导的渗透调节促进内体逃逸。纳米凝胶粗糙的3D形态赋予了优越的胶体稳定性和黏附性，支持粘膜输送。此外，PP03表现出血液相容性，未观察到溶血或出血事件，突出了其静脉给药的多功能性。这项工作强调了聚合物化学和交联效率在设计功能性RNAi纳米载体中的重要性，从而推进了基于mirna的口腔癌治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.