Engineered Exosomes with Independent Module/Cascading Function for Therapy of Parkinson's Disease by Multistep Targeting and Multistage Intervention Method

Abstract

process due to the aggressivity (e.g., electroporation or sonication methods), low yield, or poor controllability of traditional methods. [2,3] In addition, because the separation process from donor cells involves cumbersome processing steps, the weakened or lost function of exosomes in this process is difficult to be enhanced or compensated in the process of engineering. [4] In this work, the concept of "independent module/cascading function" is proposed for the controllable construction of engineered exosomes, that is, nanosized artificial module with specific functions is synthesized independently, and then selectively and controllably combined with natural exosome module in a "one-by-one" way to construct engineered exosome. The concept of "independent module" is not limited by the activity conditions of exosomes, so as to greatly enrich the preparation methods and types of artificial modules. Meantime, based on the selective and controllable combination technology between different modules, this method can effectively protect the integrity of exosome membrane structure and the activity of functional proteins and nucleic acids on membrane surface. "Cascading function" refers to endowing exosomes with new functions through rich design of artificial modules, and meeting the complex requirements of disease treatment through cascading effect, so as to play a remarkable therapeutic effect.In addition, this kind of engineered exosomes is applied to the treatment of Parkinson's disease (PD), aiming to solve the challenges of precise targeting and complex needs of PD treatment, of which the pathogenesis is complex and involves many factors and there is no effective method to completely cure it. [5] Up to now, the pathogenesis of PD can be summarized as the following process: nuclear gene mutation of dopaminergic neurons inhibits the normal hydrolysis of α-synuclein (α-syn) and promotes its aggregation in mitochondria, producing high concentration of reactive oxygen species (ROS), which further leads to enhanced expression of inducible nitric oxide synthase (iNOS) and neuroinflammation, and destroys itself and its surrounding neuronal cells. [6] Exosomes derived from stem cells have the potential to promote tissue repair and nerve regeneration, and have the ability to penetrate the blood-brain barrier Current exosome engineering methods usually lead to the damage of exosome morphology and membrane, which cannot meet the complex needs of disease treatment. Herein, the concept of an "independent module/cascading function" is proposed to construct an engineered exosome nanotherapy platform including an independent artificial module and a natural module. The artificial module with movement/chemotaxis function is first synthesized, and then it is controllably combined with the natural exosome module with "one by one" mode through a "differentiated" modification method. The whole process can not only maintain the activity of the natural exosome module, but also endows it with motion ability, so as to realize the purpose of...

Biomimetic Biomembrane Encapsulation and Targeted Delivery of a Nitric Oxide Release Platform for Therapy of Parkinson’s Disease

“…All experiments were performed in accordance with the guidelines and approved by the Ethics Committee of Nanchang University (SYXK2018-0006). The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD model has been described previously . Briefly, 6-week-old male mice were intraperitoneally injected under sterile conditions for 5 days, and then, both groups were left untreated until the experiment.…”

Biomedical Micro‐/Nanomotors: Design, Imaging, and Disease Treatment

“…To realize therapeutic application of exosome machine on PD, Wan et al proposed the concept of "independent module/cascading function" and constructed NOdriven exosome nanomotor by using natural exosome module and artificial module. [109] The artificial module was fabricated by free radical polymerization of L-arginine derivatives, which can generate NO in the PD pathological microenvironment and actively "look for" chemical attractants including up-regulated ROS and inducible nitric oxide synthase (iNOS). [110] Exosomes that are rich in transmembrane proteins and integrins have the potential to penetrate BBB and function on nerve regeneration and nervous tissue repair, which can induce anti-apoptosis and anti-inflammatory effects.…”

“…Reproduced with permission. [ 109 ] Copyright 2022, Wiley‐VCH. F) H 2 ‐propelled microswimmer for acute ischemic stroke therapy.…”

Improved intracellular delivery of exosomes by surface modification with fluorinated peptide dendrimers for promoting angiogenesis and migration of HUVECs

“…[6][7][8][9][10] In addition, the bioengineering technologies involved in the design of engineered exosomes could solve their limitations before becoming an effective therapeutic tool for various diseases, such as myocardial infarction, 11,12 cancer [13][14][15] or neurodegenerative disorders. 16,17 The cell membrane is one of the biological barriers for exogenous substances to enter cells. The intracellular delivery of exosomes appears to be inuenced by the interaction between exosomes and cell membranes.…”

“…6–10 In addition, the bioengineering technologies involved in the design of engineered exosomes could solve their limitations before becoming an effective therapeutic tool for various diseases, such as myocardial infarction, 11,12 cancer 13–15 or neurodegenerative disorders. 16,17…”