Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 182-193 http://medscipublisher.com/index.php/cge 187 isolated from different subcellular fractions, assessed by Western blotting; D and E: Detection of E1/E2 foci and EdU staining in A431 cells; F: Colocalization of E1/E2 foci with several DNA damage/repair proteins; G and H: Quantitative analysis of the proportion of cells forming E1/E2 foci and the colocalization ratio of these foci with EdU in the presence and absence of HPV16 DNA (Adapted from Bruyère et al., 2023). The study by Bruyère et al. (2023) investigated the effects of HPV16 E6/E7 on DNA damage and repair proteins. Through a series of cell experiments, the research found that these viral proteins can significantly impact the stability and subcellular distribution of specific DNA repair proteins and co-localize with E1/E2 foci associated with viral replication. These findings reveal potential carcinogenic mechanisms of HPV16 within host cells, contributing to the understanding of the molecular processes by which it induces cell transformation and cancer. 4.3 Emerging targets Recent research has identified several new molecular targets in cervical cancer that could be exploited for RNAi intervention. These emerging targets include additional viral proteins such as E5, which also contribute to the oncogenic process, and host factors involved in the regulation of the tumor microenvironment and immune response (Almeida et al., 2019; Estêvão et al., 2019). For example, the E5 oncoprotein has been shown to cooperate with E6 and E7 in promoting cellular transformation and may serve as a supplementary target for RNAi-based therapies (Estêvão et al., 2019). Furthermore, targeting the hypoxic tumor microenvironment, which can impair the effectiveness of E6/E7 inhibition, represents another promising strategy. Combining RNAi approaches with treatments that address hypoxia-induced resistance mechanisms could enhance therapeutic outcomes (Hoppe-Seyler et al., 2018). As our understanding of the molecular underpinnings of cervical cancer continues to evolve, the identification and validation of these emerging targets will be critical for the development of more effective and personalized RNAi-based therapies. 5 RNAi Delivery Strategies in Cervical Cancer Therapy 5.1 Challenges in RNAi delivery The delivery of RNA interference (RNAi) therapeutics in cervical cancer therapy faces several significant challenges. Stability, specificity, and efficient delivery to tumor sites are primary concerns. Small interfering RNAs (siRNAs) are prone to degradation by blood nucleases and rapid elimination by the kidneys, which limits their biological stability and pharmacokinetics (Gomes‐da‐Silva et al., 2012). Additionally, the negative charge and hydrophilicity of siRNAs hinder their cellular internalization, making it difficult to achieve effective delivery to target cells (Gomes‐da‐Silva et al., 2012; Miele et al., 2012). Off-target effects and the induction of the innate immune response further complicate the clinical application of RNAi-based therapies (Miele et al., 2012). 5.2 Nanoparticle-based delivery systems Nanoparticle-based delivery systems have emerged as a promising solution to overcome the challenges associated with RNAi delivery. Various types of nanoparticles, including liposomes, polymeric nanoparticles, silica, metal, graphene, dendrimers, chitosan, and organic copolymers, have been explored for siRNA delivery (Figure 3) (Xin et al., 2017; Gangopadhyay et al., 2021; Li et al., 2021). Lipid-based nanoparticles, such as stabilized nucleic acid lipid particles (SNALP), have shown potential in improving siRNA pharmacokinetics and biodistribution properties (Gomes‐da‐Silva et al., 2012; Chen et al., 2018). Li et al. (2021) studied various types of nanoparticles widely used in drug delivery, gene therapy, and bioimaging. Each nanoparticle type possesses unique physical and chemical properties, enabling tailored delivery of drugs or genetic material according to specific needs. Among them, liposomes and solid lipid nanoparticles are particularly noted for their biocompatibility and low toxicity, while gold nanoparticles and iron oxide nanoparticles have shown distinct advantages in tumor-targeted therapy and magnetic resonance imaging. The design and application of these nanocarriers have significantly enhanced drug delivery efficiency and targeting specificity, driving the advancement of nanomedicine. Nanoparticles offer several advantages for RNAi delivery. They can protect siRNAs from degradation, enhance cellular uptake, and improve the bioavailability of the therapeutic agents (Miele et al., 2012; Young et al., 2016).
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