Review of microRNA Regulation and Delivery in Breast Cancer: Potential and Limits of Multi-Target Therapy
Background
A review published in Cancers summarizes strategies for targeting multiple gene-regulatory pathways in breast cancer with microRNAs (miRNAs), along with development challenges. It brings together miRNA biology and regulation and delivery technologies, and examines barriers to clinical translation. It does not report new experiments or treatment effects in patients.
Breast cancer has diverse molecular features that affect treatment response, while treatment resistance and metastasis complicate disease management. miRNAs are small non-coding RNAs that induce degradation of target messenger RNA (mRNA) or inhibit protein synthesis. Their ability to regulate multiple targets allows them to participate in processes such as cancer-cell proliferation, cell death, and invasion. However, the regulatory effects of the same miRNA can vary across breast cancer subtypes. Detecting differences in expression must be distinguished from validating function as a therapeutic target.
Key findings
The strategies summarized in the review fall into two groups: replenishing deficient tumor-suppressive miRNAs and inhibiting cancer-promoting miRNAs. Synthetic miRNA mimics imitate the activity of cellular miRNAs, while expression vectors are designed to make cells produce miRNAs. Anti-miRNA oligonucleotides (AMOs) bind complementarily to mature miRNAs and block their function. miRNA sponges use repeated binding sites to sequester miRNAs, reducing their interactions with target mRNAs.
CRISPR-based technologies are also used in functional studies. CRISPR-Cas9 can disrupt genomic regions encoding miRNAs, while CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) are approaches for increasing and decreasing transcription, respectively. Activation does not always lead to an anticancer effect. In a triple-negative breast cancer (TNBC) cell-line study cited in the review, transcriptional activation of miR-3662 promoted proliferation and migration, whereas transcriptional repression reduced traits associated with tumor growth.
Delivery vehicles protect regulatory molecules and carry them into tumor cells. Lipid and polymer nanoparticles are used for RNA protection and intracellular delivery, but challenges involving immune responses, toxicity, and stability remain, depending on the formulation. Escape from endosomes, vesicles within cells, after cellular uptake was also identified as a barrier. Inorganic nanoparticles offer structural stability and advantages for surface modification, but their long-term biocompatibility needs to be established. The review’s comparisons summarize platform-specific properties reported in prior literature; they are not results from the authors testing which delivery vehicle performed better under identical conditions.
Implications and outlook
Potential combinations with existing treatments have been suggested mainly in cell and animal studies. The review describes a BRCA1-deficient breast cancer xenograft model in which tumor growth was inhibited when a miR-451 mimic and a PARP1 inhibitor were administered together in cationic liposomes. Whether the same effect occurs in patients remains to be tested separately.
Experience with development in humans highlights the importance of safety. According to the review, MRX34, a liposomal miR-34a mimic, entered a phase 1 trial in patients with advanced solid tumors, but the trial was stopped because of immune-related adverse events. This experience indicated the possibility of delivering miRNA to humans, but it does not establish efficacy as a breast cancer treatment.
The ability of miRNAs to regulate multiple pathways offers therapeutic potential while also being a source of off-target effects. Further development needs to address subtype-specific target validation, tumor-selective delivery, appropriate dosing, and immune toxicity together. Integration with precision medicine was proposed as a research direction contingent on such validation. The study type and evidence for each technology can be found in the paper abstract and bibliographic record and the publicly available full-text materials.
Breast cancer is a highly heterogeneous malignancy that remains one of the leading causes of cancer-related mortality among women worldwide. Despite significant advances in breast cancer research and therapy, disease heterogeneity, treatment resistance, and metastatic progression remain major obstacles to effective disease management. Among the molecular regulators involved in breast cancer, microRNAs (miRNAs) have been recognized as critical post-transcriptional regulators of gene expression, functioning as either oncogenes or tumor suppressors. By modulating the expression of target RNAs, miRNAs control key biological processes involved in tumor initiation and progression, including cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition (EMT), invasion, and metastasis. To investigate miRNA function and explore their therapeutic potential, a wide range of approaches have been developed to modulate miRNA expression. These include gain-of-function strategies, like miRNA mimics, miRNA expression vectors, and CRISPR activation (CRISPRa), as well as loss-of-function approaches, including anti-miRNA oligonucleotides (AMOs), miRNA sponges, CRISPR-Cas9-mediated gene knockout, and CRISPR interference (CRISPRi). This review provides a comprehensive overview of the biological roles of miRNAs in breast cancer and discusses current technologies for miRNA modulation, their molecular mechanisms, experimental and therapeutic applications, and associated limitations. In addition, it summarizes recent advances in miRNA delivery systems, including viral vectors, organic nanoparticles, and inorganic nanocarriers, highlighting their potential to improve delivery efficiency, target specificity, and facilitate clinical translation. Finally, the review discusses future perspectives, emphasizing the transition from single-target interventions toward network-level regulation and the integration of miRNA-based strategies into precision oncology to support the development
This review gives research teams developing candidate combinations of miRNA modulators and existing anticancer drugs criteria for evaluating target and delivery-vehicle choices. For example, when evaluating a TNBC candidate, teams could confirm the miRNA’s function in that subtype and consider a preclinical design comparing a drug-alone group with a combination group. Examining delivery efficiency, effects on normal tissues, and immune responses alongside changes in tumor growth would build evidence for assessing a candidate’s strengths and limitations. This is an example of applying the development challenges identified in the review to study design. The discontinuation of the MRX34 trial shows that anticancer activity alone cannot establish clinical safety. The review’s current practical use is to help prioritize follow-up validation of targets, delivery vehicles, and combination strategies rather than to recommend treatments for patients.