Engineered EV-Mimetic Nanoparticles as Therapeutic Delivery Vehicles for High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy among women. Several obstacles impede the early diagnosis and effective treatment options for ovarian cancer (OC) patients, which most importantly include the development of platinum-drug-resistant strains. Currently, extensive efforts are being put into the development of strategies capable of effectively circumventing the physical and biological barriers present in the peritoneal cavity of metastatic OC patients, representing a late stage of gastrointestinal and gynecological cancer with an extremely poor prognosis. Naturally occurring extracellular vesicles (EVs) have been shown to play a pivotal role in progression of OC and are now being harnessed as a delivery vehicle for cancer chemotherapeutics. However, there are limitations to their clinical application due to current challenges in their preparation techniques. Intriguingly, there is a recent drive towards the use of engineered synthetic EVs for the delivery of chemotherapeutics and RNA interference therapy (RNAi), as they show the promise of overcoming the obstacles in the treatment of OC patients. This review discusses the therapeutic application of EVs in OC and elucidates the potential use of engineered EV-mimetic nanoparticles as a delivery vehicle for RNAi therapy and other chemotherapeutics, which would potentially improve clinical outcomes of OC patients.

Extracellular vesicle contents as non-invasive biomarkers in ovarian malignancies

“…124 These exosome mimetics have great therapeutic potential as they can be effectively produced in large quantities to aid in drug delivery. 125 Several therapeutic approaches are being developed where EVs could be employed for cancer therapy. One such approach is ExoSTING, in which an engineered EV is loaded with cyclic dinucleotide agonists of the stimulator of interferon genes (STING), which enhances the potency of cyclic dinucleotide agonists, while avoiding the systemic inflammation and failure to establish immune memory, which occurs when cyclic dinucleotide agonists are administered directly into tumors.…”

“… 124 These exosome mimetics have great therapeutic potential as they can be effectively produced in large quantities to aid in drug delivery. 125 …”

Non-Coding RNAs Delivery by Small Extracellular Vesicles and Their Applications in Ovarian Cancer

“…Second, they can be absorbed by recipient cells, thereby altering cellular processes. Third, sEVs have high histocompatibility and can reduce immune clearance in drug delivery ( Kamerkar et al, 2017 ; Al-Dossary et al, 2021 ). As drug-delivery vesicles, sEVs can penetrate through anatomical barriers and have been shown to deliver miRNAs ( Jc Bose et al, 2018 ), siRNAs ( Kamerkar et al, 2017 ), CRISPR/Cas9 ( Yao et al, 2021 ), and chemotherapeutic drugs ( Qiu et al, 2019 ) safely and effectively in animal models ( Figure 3 ).…”

Hydroxychloroquine Enhances Cytotoxic Properties of Extracellular Vesicles and Extracellular Vesicle-Mimetic Nanovesicles Loaded with Chemotherapeutics

“…On the other hand, EMNVs are more compatible with upscaling procedures of the final product [14] and characterized by a faster and cost-effective synthesis, while their manipulation and loading options (including pre-synthesis genetic engineering modifications on the source cells) are comparable to EVs [10]. Still, the practical use of EMNVs should be considered with caution because of potential contamination with unwanted cellular materials (i.e., nucleic acids) that can eventually affect their immunological tolerance [15]. In consideration of the inherent differences at the basis of the EV and EMNV synthesis, it is reasonable to expect that their therapeutic properties can change both in terms of loading yield and cytostatic properties.…”