Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.
Center for Synthetic Biology, Northwestern University, Evanston, IL, 60208, USA.
Small. 2022 May;18(19):e2200125. doi: 10.1002/smll.202200125. Epub 2022 Apr 7.
The ability of pathogens to develop drug resistance is a global health challenge. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an urgent need wherein several variants of concern resist neutralization by monoclonal antibody (mAb) therapies and vaccine-induced sera. Decoy nanoparticles-cell-mimicking particles that bind and inhibit virions-are an emerging class of therapeutics that may overcome such drug resistance challenges. To date, quantitative understanding as to how design features impact performance of these therapeutics is lacking. To address this gap, this study presents a systematic, comparative evaluation of various biologically derived nanoscale vesicles, which may be particularly well suited to sustained or repeated administration in the clinic due to low toxicity, and investigates their potential to inhibit multiple classes of model SARS-CoV-2 virions. A key finding is that such particles exhibit potent antiviral efficacy across multiple manufacturing methods, vesicle subclasses, and virus-decoy binding affinities. In addition, these cell-mimicking vesicles effectively inhibit model SARS-CoV-2 variants that evade mAbs and recombinant protein-based decoy inhibitors. This study provides a foundation of knowledge that may guide the design of decoy nanoparticle inhibitors for SARS-CoV-2 and other viral infections.
病原体产生耐药性的能力是全球健康面临的一个挑战。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 就是一个紧迫的例子，其几种变体对单克隆抗体 (mAb) 疗法和疫苗诱导的血清具有耐药性。诱饵纳米粒子——模拟细胞结合并抑制病毒粒子的纳米粒子——是一类新兴的治疗药物，可能克服这种耐药性挑战。迄今为止，对于设计特征如何影响这些治疗药物的性能，还缺乏定量的了解。为了弥补这一空白，本研究系统地比较了各种生物衍生的纳米级囊泡，由于其毒性低，这些囊泡可能特别适合在临床上进行持续或重复给药，并研究了它们抑制多种模型 SARS-CoV-2 病毒粒子的潜力。一个关键的发现是，这些颗粒在多种制造方法、囊泡亚类和病毒诱饵结合亲和力下表现出强大的抗病毒功效。此外，这些模拟细胞的囊泡还能有效抑制逃避 mAb 和重组蛋白诱饵抑制剂的模型 SARS-CoV-2 变体。本研究提供了一个知识基础，可能为 SARS-CoV-2 和其他病毒感染的诱饵纳米粒子抑制剂的设计提供指导。
