Wendler Astrid, James Nicholas, Jones Michael H, Pernstich Christian
Cell Guidance Systems Ltd., Maia Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
Biodes Res. 2021 May 14;2021:9816485. doi: 10.34133/2021/9816485. eCollection 2021.
Many cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages, and microglia are among the so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as nonprofessional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune responses, wound healing, and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale cocrystalline protein depots, known as PODS®, that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by nonprofessional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding nonphagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.
许多细胞具有通过吞噬作用吞噬和纳入颗粒的能力。这种活跃过程是微生物以及高等生物的特征。在哺乳动物中，单核细胞、巨噬细胞和小胶质细胞属于所谓的专职吞噬细胞。此外，成纤维细胞和软骨细胞等细胞被归类为非专职吞噬细胞。专职吞噬细胞在先天免疫和适应性免疫反应、伤口愈合以及组织稳态中都发挥着重要作用。因此，这些细胞作为治疗一系列疾病的治疗干预靶点和载体受到越来越多的研究。众所周知，专职吞噬细胞很难转染，这限制了对它们的研究和操作。因此，人们的努力已转向开发纳米颗粒，以便通过吞噬作用将货物递送至吞噬细胞。然而，这种方法面临重大技术挑战，尤其是对于蛋白质货物而言。我们专注于开发纳米级共结晶蛋白质贮库，即所谓的PODS®，其包含蛋白质货物，包括细胞因子。在此，我们表明PODS很容易被非专职以及专职吞噬细胞吞噬，并且具有诸如货物高度持续释放等特性，这表明其在研究和利用吞噬细胞进行药物递送方面具有潜在用途。摄取PODS的单核细胞和巨噬细胞保持正常特征，包括强烈的趋化反应。此外，负载细胞分泌的PODS-细胞因子货物水平足以调节周围非吞噬细胞的行为。此处呈现的结果证明了PODS纳米颗粒作为一种新型分子工具在研究和操纵吞噬细胞以及开发用于治疗癌症和其他疾病的特洛伊木马免疫治疗策略方面的潜力。
