Nanoquercetin and Extracellular Vesicles as Potential Anticancer Therapeutics in Hepatocellular Carcinoma

Abstract

Despite world-class sophisticated technologies, robotics, artificial intelligence, and machine learning approaches, cancer-associated mortalities and morbidities have shown continuous increments posing a healthcare burden. Drug-based interventions were associated with systemic toxicities and several limitations. Natural bioactive compounds derived nanoformulations, especially nanoquercetin (nQ), are alternative options to overcome drug-associated limitations. Moreover, the EVs-based cargo targeted delivery of nQ can have enormous potential in treating hepatocellular carcinoma (HCC). EVs-based nQ delivery synergistically regulates and dysregulates several pathways, including NF-κB, p53, JAK/STAT, MAPK, Wnt/β-catenin, and PI3K/AKT, along with PBX3/ERK1/2/CDK2, and miRNAs intonation. Furthermore, discoveries on possible checkpoints of anticancer signaling pathways were studied, which might lead to the development of modified EVs infused with nQ for the development of innovative treatments for HCC. In this work, we abridged the control of such signaling systems using a synergetic strategy with EVs and nQ. The governing roles of extracellular vesicles controlling the expression of miRNAs were investigated, particularly in relation to HCC.

Keywords: delivery; extracellular vesicles; hepatocellular carcinoma; inhibitors; quercetin nanoparticles; therapeutic targets.

Figure 1

Estimated age-standardized incidence rates (ASR) (worldwide) for liver cancer, both sexes and all ages, in 2020. Adapted from [3].

Figure 2

Estimated age-standardized mortality rates (worldwide) in 2020 for liver cancer, both sexes and all ages. Adapted from [3].

Figure 3

Mortality-ASR (worldwide) vs. incidence-ASR (worldwide) in 2020 for both sexes and all ages. Adapted from [3].

Figure 4

Barcelona Clinic Liver Cancer (BCLC) staging system.

Figure 5

The most important signaling pathways affected by quercetin during cancer prevention. (A) Wnt/β catenin pathway—quercetin inhibits β-catenin translocation to the nucleus; (B) PI3K/Akt pathway—inhibition of phosphorylation of PI3K, Akt, and S6K; (C) JAK/STAT pathway—inhibition of p-STAT formation; (D) MAPK pathway—induced phosphorylation of p38, JNK, and ERK; (E) p53 pathway—induced phosphorylation of p53 and induction of apoptosis. Adapted from [99] under the terms of the Creative Commons Attribution License (CC BY).

Figure 6

Hepatocellular carcinoma regulations by EVs. Adapted from Ref. [111] under the terms of the Creative Commons Attribution License (CC BY). TAMs, tumor-associated macrophages; CSCs, cancer stem cells; CAFs, cancer-associated fibroblasts; EMT, epithelial–mesenchymal transition.