Aug 2026· DARU Journal of Pharmaceutical Sciences· Vol 34· 0 citations· 225 references
Medicine
TL;DR
Challenges such as scalable production, cargo heterogeneity, and regulatory considerations remain, but ongoing advances in exosome engineering and patient-derived vesicles are poised to overcome these barriers.
Small interfering RNA (siRNA) therapeutics have emerged as a transformative approach for sequence-specific gene silencing, offering the potential to treat a broad spectrum of diseases by selectively suppressing disease-associated genes. However, the clinical translation of siRNA remains limited by rapid enzymatic degradation, poor cellular uptake, inadequate endosomal escape, and off-target effects, necessitating the development of efficient delivery systems. Extracellular vesicles (EVs) have gained considerable attention as natural nanocarriers owing to their excellent biocompatibility, low immunogenicity, intrinsic targeting capability, and ability to protect therapeutic cargo while traversing complex biological barriers. This review comprehensively discusses the biological characteristics of EVs, the molecular basis of RNA interference, and the major challenges associated with siRNA delivery [Fig. 1]. Recent advances in EV engineering, including cargo-loading strategies such as electroporation, sonication, extrusion, parent-cell engineering, and microfluidic approaches, together with surface functionalization using peptides, antibodies, aptamers, and hybrid nanoplatforms, are critically evaluated for improving targeting specificity and intracellular delivery. Furthermore, the therapeutic applications of engineered EV-mediated siRNA delivery in cancer, neurological disorders, liver diseases, cardiovascular diseases, inflammatory disorders, and infectious diseases are systematically summarized, highlighting their potential to enhance gene silencing while minimizing systemic toxicity. Current challenges related to large-scale manufacturing, cargo-loading efficiency, standardization, quality control, regulatory approval, and clinical translation are also discussed, together with emerging technologies involving synthetic biology, genome engineering, artificial intelligence, and multifunctional hybrid vesicles. Overall, engineered extracellular vesicles represent a highly versatile and biologically inspired platform for targeted siRNA delivery, providing a promising foundation for the development of next-generation precision RNA therapeutics and accelerating the clinical translation of gene-silencing strategies.
G. S. Amrish Varshan, S. Namasivayam· Nanomedicine: Nanotechnology...· 0 citations
Abstract Gene silencing by RNA interference (RNAi) has emerged as a promising strategy for cancer therapy. Small interfering RNA (siRNA), a class of small regulatory RNAs that recognize and degrade complementary target messenger RNAs (mRNAs) in a sequence-specific manner at the post-transcriptional level, plays a critical role in regulating gene expression. However, the in vivo delivery of siRNA remains a formidable challenge due to its poor physiological stability, susceptibility to enzymatic degradation, inability to efficiently cross cellular membranes, non-specific off-target effects, and immunostimulation. Overcoming these barriers and enhancing the gene silencing efficiency of siRNA in target cells is essential for the clinical translation of RNAi technology. In recent years, tumor microenvironment (TME)-responsive nanocarriers have attracted considerable attention as a strategy to improve siRNA stability, enhance its enrichment and penetration at tumor sites, facilitate cellular uptake, and promote efficient gene silencing. This review comprehensively summarized the design principles and functional characteristics of TME-responsive siRNA delivery nanocarriers, with a focus on five major stimuli: pH, hypoxia, enzymes, glutathione (GSH), and reactive oxygen species (ROS). We critically analyze the advantages and limitations of existing nanocarrier systems, provide comparative insights through summary tables, and discuss future directions including multi-stimuli-responsive systems, combination therapies, and clinical translation challenges. This review aims to provide a systematic framework for understanding and advancing TME-responsive siRNA nanocarriers for tumor therapy.
Xiao-Xia Zhu, Gong-Hu Zhang, Lin Li et al.· International Journal of Nan...· 0 citations
Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research, and this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context.
Gheysar Seifollahnezhad, B. Erdağ· Experimental oncology· 0 citations
Background/Objectives: RNA interference (RNAi) represents a promising therapeutic approach for silencing oncogenes involved in cancer progression by utilizing small interfering RNA (siRNA). However, siRNA requires an efficient delivery system to overcome cellular uptake and endosomal escape barriers. This study aimed to evaluate a multifunctional tandem peptide, GE11-599, designed to enhance the targeted delivery of siRNA and maintain its bioactivity in glioblastoma (GBM) cells. Methods: The GE11-599 peptide, consisting of an EGFR-targeting GE11 motif and a 599 fusogenic domain, was complexed with siRNA via electrostatic interactions to form nanoparticles. We assessed nanoparticle physicochemical properties, protection of siRNA from serum and RNase degradation, and cellular uptake in two GBM cell lines (U118MG and U87MG). Mechanistic studies evaluated receptor-mediated endocytosis and the subsequent escape from endosomes. Functional assays quantified STAT3 gene silencing and downstream effects on cell migration following treatment with GE11-599–siSTAT3 complexes. Results: GE11-599 formed positively charged, monodisperse nanoparticles capable of protecting siRNA from degradation. The tandem peptide significantly enhanced cellular internalization through EGFR-mediated endocytosis and facilitated endosomal escape of siRNA. Treatment with GE11-599–siSTAT3 resulted in robust gene silencing, achieving up to an 80% reduction in STAT3 mRNA expression. Downstream functional assessment showed a 40% decrease in migration in GBM cells treated with GE11-599–siSTAT3 complexes. Conclusions: The GE11-599 tandem peptide effectively enhances cell-specific internalization and endosomal escape of siRNA in GBM cells, resulting in increased siRNA bioactivity and functional gene silencing. These findings support GE11-599 as a promising siRNA delivery platform for targeting EGFR-expressing cancers.
Jessica R. Boulos, Karen Russi, Jordan Kinnitt et al.· Pharmaceutics· 0 citations
The goal of this review is to outline a realistic pathway featuring proof-of-concept research, through discoveries to the creation of manufacturable, safe, and effective exosome/CRISPR therapeutics that can trigger durable therapeutic responses in resistant malignancies.
Abstract Breast cancer remains one of the leading causes of cancer-related mortality worldwide, with its marked molecular heterogeneity and therapeutic resistance continuing to limit long-term clinical success. Although advances in targeted therapies have improved patient outcomes, tumor recurrence, systemic toxicity, and drug resistance remain major clinical challenges. MicroRNAs (miRNAs) have emerged as promising therapeutic molecules because they regulate multiple oncogenic pathways involved in proliferation, apoptosis, epithelial–mesenchymal transition, metastasis, and therapy resistance. Preclinical studies have demonstrated that restoring tumor-suppressive miRNAs or inhibiting oncogenic miRNAs can suppress tumor growth, reduce metastatic potential, and enhance treatment sensitivity. However, their clinical application is hindered by poor stability, rapid enzymatic degradation, limited cellular uptake, and inefficient intracellular delivery. Recent advances in nanomedicine have enabled the development of multifunctional nanoparticle platforms that effectively address these limitations. Lipid nanoparticles, polymeric nanoparticles, dendrimers, and inorganic nanocarriers have demonstrated the ability to protect miRNAs from degradation, prolong systemic circulation, enhance tumor-specific accumulation, facilitate cellular uptake, and promote endosomal escape for efficient cytoplasmic release. Moreover, targeted and stimuli-responsive nanocarriers, as well as combination strategies integrating miRNAs with conventional therapeutics, have shown encouraging therapeutic efficacy in preclinical breast cancer models. This review summarizes recent advances in nanoparticle-mediated miRNA delivery systems for breast cancer, highlighting the biological roles of therapeutic miRNAs, the design and performance of current nanocarriers, and their translational potential. Current challenges and future perspectives for the clinical implementation of miRNA-based nanomedicine are also discussed. Overall, nanoparticle-enabled miRNA therapeutics represent a promising platform for advancing precision medicine and next-generation personalized treatment strategies for breast cancer.
Övünç Efe Lukumci, D. Cansaran-Duman, Pelin Mutlu· International Journal of Nan...· 0 citations
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