使用逐层方法开发针对EGFR+膀胱癌细胞的基于弹性蛋白样多肽的核酸递送系统
Development of an Elastin-like Polypeptide-Based Nucleic Acid Delivery System Targeted to EGFR+ Bladder Cancer Cells Using a Layer-by-Layer Approach
影响因子:5.40000
分区:化学1区 Top / 有机化学1区 高分子科学1区 生化与分子生物学2区
发表日期:2024 Sep 09
作者:
Aayush Aayush, Saloni Darji, Kiera M Estes, Emily Yeh, David H Thompson
摘要
基于核酸（NA）的疗法正在通过控制遗传水平的细胞功能的能力来彻底改变生物医学研究。这项工作证明了使用逐层（LBL）配方方法的多功能弹性蛋白样多肽（ELP）载体系统，该方法可提供从siRNA到质粒的大小范围的Na cargos。可以重新配置系统的组件以调节载体的生化和生物物理特性，以吸引生物靶标的独特特征。我们显示了在鼠和人膀胱肿瘤细胞系中LBL ELP核酸纳米颗粒（LENN）的物理表征和生物学性能。由于尿液不断流入膀胱，因此很难靶向膀胱肿瘤，从而导致接触时间较低（通常<2 h），用于通过静脉内输送的治疗剂。 Lenn复合物在30分钟内与膀胱肿瘤细胞结合，并在60分钟内迅速内化，以释放其NA货物。我们的数据表明，已经创建了一个易于适应的NA分机系统，其靶向能力，货物尺寸和拆卸动力学具有灵活性。这种方法为患有效率低下和物理化学不稳定性的脂质纳米颗粒制剂提供了替代途径，或者是由于制造和免疫排斥挑战所困扰的病毒载体。这种敏捷的基于ELP的纳米载体为核酸递送提供了替代途径，该途径使用可生物制造，可生物降解，生物相容性和高度可调的载体，能够通过与过表达的细胞表面受体互动来靶向细胞。
Abstract
Nucleic acid (NA)-based therapies are revolutionizing biomedical research through their ability to control cellular functions at the genetic level. This work demonstrates a versatile elastin-like polypeptide (ELP) carrier system using a layer-by-layer (LbL) formulation approach that delivers NA cargos ranging in size from siRNA to plasmids. The components of the system can be reconfigured to modulate the biochemical and biophysical characteristics of the carrier for engaging the unique features of the biological target. We show the physical characterization and biological performance of LbL ELP nucleic acid nanoparticles (LENNs) in murine and human bladder tumor cell lines. Targeting bladder tumors is difficult owing to the constant influx of urine into the bladder, leading to low contact times (typically <2 h) for therapeutic agents delivered via intravesical instillation. LENN complexes bind to bladder tumor cells within 30 min and become rapidly internalized to release their NA cargo within 60 min. Our data show that a readily adaptable NA-delivery system has been created that is flexible in its targeting ability, cargo size, and disassembly kinetics. This approach provides an alternative path to either lipid nanoparticle formulations that suffer from inefficiency and physicochemical instability or viral vectors that are plagued by manufacturing and immune rejection challenges. This agile ELP-based nanocarrier provides an alternative route for nucleic acid delivery using a biomanufacturable, biodegradable, biocompatible, and highly tunable vehicle capable of targeting cells via engagement with overexpressed cell surface receptors.