以外覆生物膜之奈米載體發展抗流感病毒之藥物與疫苗
Biomembrane cloaked nanoparticles for anti-influenza drug delivery and vaccination
The objective of the present proposal is to utilize a novel cell membrane coated nanoparticle technology to improve antiviral countermeasures, including the development of virus-targeted antivirals and vaccine with better safety and effectiveness. Through the NTU-AS collaboration, we have published successful development of two unique nanoformulations, including 1) a red blood cell membrane coated magnetic nanoparticle for the capture and isolation of influenza virus for improved detection (ACS Applied Materials and Interfaces, 2017) and 2) a vATPase inhibitor loaded nanoformulation for inhibiting viral infection (International Journal of Nanomedicine, 2018). These works highlight successful integration of the virology expertise of Dr. Chen at the National Taiwan University and of the nanotechnology expertise of Dr. Hu at Academia Sinica. The collaboration has also spurred new project directions based on the versatility of the cell membrane coated nanoparticle platform. In one direction, we are exploiting the virus targeting capability of the cell-like nanoparticles to improve antiviral delivery. To this end, we have successfully shown that erythrocyte membrane coated nanoparticles can not only bind to influenza virions but also to influenza-infected cells, which display hemagglutinin on their surfaces. In parallel, we are also applying the biomembrane coating technology for vaccine development. To enhance vaccine formulations against H7N9 avian influenza virus, we are integrating recombinant virus-like particle technology with synthetic polymeric nanoparticle technology to construct adjuvant-loaded virus-like particles with the aim of enhancing immune activation. As shown in the figure, we have successfully incorporated a toll like receptor 7/8 agonist, R848, into a biodegradable, PLGA-based nanoparticle for subsequent coating with H7N9 VLP. Rigorous physicochemical characterizations have shown that the VLP-coated nanoparticles display surface hemagglutinin and neuraminidase similarly as native virions. The adjuvant-loaded nanoparticles have also been quantified to contain approximately 10,000 R848 molecules per particle. The adjuvant-loaded virus-like particles are expected to show improved safety and effectiveness via localized and synchronized antigen and adjuvant delivery. We anticipate the nanoparticles to elicit potent humoral and cellular immunity upon planned immunization in mice.
本計畫的目的是創新利用以細胞膜包覆的奈米顆粒技術來開發新型抗病毒對策，開發項目包括具有更好安全性和有效性的病毒標靶性抗病毒藥劑和疫苗。通過NTU-AS 合作，我們已成功開發並發表了兩種獨特的奈米製劑，包括 1) 紅細胞膜包覆的磁性奈米顆粒用於捕獲和分離流感病毒以改進病原快篩之檢測（ACS Applied Materials and Interfaces, 2017）和2) 加載vacuolar ATPase 抑制劑的奈米藥物用於抑制病毒感染（International Journal of Nanomedicine, 2018）。本合作也基於細胞膜包覆的奈米顆粒平台之多功能性激發出了新的項目方向。在其中一個方向上，我們正在利用仿細胞奈米粒子的病毒靶向能力來改善抗病毒藥劑的遞送。在此項目中，我們已經成功地證明，紅血球膜包被的奈米顆粒不僅可以與流感病毒粒子結合，還可以與流感病毒感染的細胞結合。與此同時，我們也將生物膜奈米技術應用於疫苗開發。為了增強針對 H7N9 流感病毒的疫苗製劑，我們將類病毒顆粒技術與合成聚合物奈米顆粒結合，以構建載有佐劑的病毒樣顆粒，以增強免疫激活。如圖所示，目前我們已成功將 Toll 樣受體 7/8 致活劑 R848 包裹入可生物降解的 PLGA 奈米顆粒中，並以 H7N9 類病毒顆粒膜包覆於外作為抗原，預期載有佐劑的病毒樣顆粒透過同步的抗原和佐劑遞送，能有效引發的保護性的體液和細胞免疫，產生更高的疫苗安全性和效性。