Department of Chemistry & Purdue Institute for Cancer Research, Purdue University, Bindley Bioscience Center, West Lafayette, Indiana 47907, United States.
Biomacromolecules. 2024 Sep 9;25(9):5729-5744. doi: 10.1021/acs.biomac.4c00165. Epub 2024 Aug 26.
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 bL LP ucleic acid anoparticles (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.
核酸（NA）为基础的治疗方法正在通过其在遗传水平上控制细胞功能的能力彻底改变生物医学研究。这项工作展示了一种使用层层（LbL）配方方法的多功能弹性蛋白样多肽（ELP）载体系统，该系统可输送大小从 siRNA 到质粒的 NA 有效负载。该系统的组件可以重新配置，以调节载体的生化和物理特性，从而利用生物靶标的独特特征。我们展示了在鼠和人膀胱肿瘤细胞系中 bL LP ucleic 酸纳米颗粒（LENNs）的物理特性和生物学性能。由于尿液不断涌入膀胱，导致通过膀胱内灌注递送的治疗剂的接触时间（通常<2 小时）很短，因此靶向膀胱肿瘤很困难。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 有效负载。我们的数据表明，已经创建了一种适应性强的 NA 递送系统，该系统在靶向能力、有效负载大小和组装动力学方面具有灵活性。这种方法为脂质纳米颗粒制剂（存在效率和物理化学不稳定性的问题）或病毒载体（存在制造和免疫排斥挑战的问题）提供了另一种选择。这种灵活的基于 ELP 的纳米载体提供了一种使用生物制造、可生物降解、生物相容和高度可调的载体进行核酸传递的替代途径，该载体能够通过与过度表达的细胞表面受体的结合来靶向细胞。
