Engineering Cellular Vesicles for Immunotherapy

Abstract

Immunotherapy has become a crucial strategy for cancer and infectious diseases due to its ability to leverage the power of the immune system to combat diseases, particularly when conventional therapeutic options have been ineffective. Nonetheless, low immune response rates and immune-related adverse events (irAEs) remain significant challenges for immunotherapeutics. Therefore, there is an urgent need to develop new strategies for improving the immunotherapy. Extracellular vesicles (EVs), secreted by living cells, are small membrane-bound vesicles. Their size varies from 30 to 150 nm in diameter and can be found in various bodily fluids, including blood, tears, and breast milk. They have attracted extensive attention in immunotherapy due to their integral role in essential physiological and pathological processes. Despite their potential, EVs face limitations, including low productivity and high costs, hindering their clinical applications. These issues have recently been addressed with the advent of EV mimics. EV mimics are artificially produced nanoscale vesicles. Compared to EVs, they offer superior production efficiency while maintaining similar biological properties. EV mimics are obtained by physical methods from natural cells. Methods such as serial extrusion, sonication, and electroporation are now used to produce synthetic EV mimics, making them viable for immunotherapy applications. Building on this, we have developed various EV mimics from different cell sources for immunotherapy and engineering natural EVs and EV mimics using chemical and bioengineering strategies like biochemical conjugation, genetic engineering, and membrane hybridization. These engineered natural EVs and EV mimics have controllable immunomodulatory properties, capable of modulating (i.e., boosting or inhibiting) immunity for the treatment of cancer and infectious diseases.

In this Account, we categorize both natural EVs and synthetic EV mimics under the umbrella term “cellular vesicles (CVs)” due to their similar structural and functional characteristics. We focus on recent advancements of CVs for immunotherapy, primarily work from our research group, and then summarize three main CV preparation methods, highlighting the microfluidic method developed by our team, which enables stable and efficient preparation. Following that, we outline engineering strategies for CVs to guide researchers in selecting the methods according to their needs. Additionally, we detail our progress in using CVs for treating cancer and infectious diseases. Finally, potential challenges and our future direction for overcoming these obstacles are also discussed. This Account highlights the development of engineered CVs, offering valuable insights into engineering strategies of personalized CVs and shedding new light on the therapeutic potential of biomimetic nanomaterials for cancer and infectious diseases.