Nucleic Acid Therapy and microRNAs

Nucleic acid therapy (NAT) is the latest medical trend for treating various diseases with synthetic nucleic acids. This approach includes using antisense oligonucleotides, small interfering RNA (siRNA), and microRNA (miRNA). Such technologies were initially developed for rare genetic and metabolic disorders, but they have since been used for more common diseases, including inflammatory and infectious skin diseases.

MicroRNA therapy, which emerged as an experimental method in the early 2000s, relies on regulating gene expression by interacting small RNAs with microRNA targets. This approach has already been used in treating chronic skin ulcers and hypertrophic scars and, in recent years, has been actively investigated in the context of acne [1].

Pathogenetic role of microRNAs in the treatment of acne

Acne (acne vulgaris) is an inflammatory skin disease caused by complex interactions between the bacterium Cutibacterium acnes (C. acnes), sebocytes, and the immune system. The pathogenesis of acne includes hyperkeratinization, excessive sebum production, inflammation, and C. acnes biofilm formation [2]. In this context, microRNAs play an important role as regulators of inflammatory processes.

Let us name the main microRNAs studied in the context of acne:

1. miR-146a-5p. This microRNA regulates inflammation by inhibiting the expression of key mediators of the Toll-like receptor 2 (TLR2) signaling pathway, such as IRAK1 and TRAF6. Elevation of miR-146a-5p reduces the production of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α, making it a promising target for therapy [3].
2. miR-21-5p. Associated with inflammation in keratinocytes through decreased activity of tissue inhibitor of metalloproteinase 3. It is believed that its suppression can reduce the level of active TNF-α and reduce inflammation [4].
3. miR-223-3p. Involved in the regulation of IL-6 production and other inflammatory mediators. Increased levels of this microRNA may be a compensatory mechanism to restore homeostasis [5].
4. miR-150-5p. This microRNA is associated with immune differentiation and modulates IL-10 expression, which may have anti-inflammatory effects [6].

Potential therapeutic strategies

 The use of microRNAs for the treatment of acne can be realized through:

• Increasing the level of miR-146a-5p using its mimics (mimics are synthetic analogs that repeat the nucleotide sequence of their corresponding microRNA to increase the missing microRNA due to the disease). This will help reduce inflammation caused by acnes biofilms.
• Suppression of miR-21-5p to reduce the production of active TNF-α.
• Combination approaches involve using microRNA and antibiotics or isotretinoin to accelerate the elimination of inflammatory elements of acne.

How to deliver microRNAs to targets in the skin

Efficient delivery of microRNAs to target skin cells such as sebocytes and keratinocytes is critical. The main delivery strategies include:

• Lipid conjugates. MicroRNAs can be bound to lipids, such as cholesterol or docosanoic acid, to improve their penetration into lipophilic skin structures, including sebaceous glands. For example, such conjugates have already been used in studies on microRNA delivery to muscle tissues [7].
• Nanoparticles and liposomes. Lipid- or polymer-based nanoparticles protect the microRNA from degradation and its gradual release. In dermatology, deformable liposomes and liquid crystalline nanosystems are effective delivery systems for active ingredients into the skin.
• Ionic liquids. New developments include using ionic liquids to facilitate the penetration of microRNAs through the skin's stratum corneum. This approach allows the delivery of microRNAs, siRNAs, and other oligonucleotides into the epidermis and dermis [7].
• Spherical nucleic acids. Complexes formed around nanoparticles provide improved interaction with cell membranes, making them a promising tool for targeted delivery of microRNAs.
• Cell-penetrating peptides (CPP). CPPs improve the intrinsic delivery of microRNAs into keratinocytes and sebocytes, minimizing losses to the extracellular space.

No products with microRNAs for treating skin diseases are on the market as development is in the clinical research phase. However, there are prototypes and experimental drugs available:

• Remlarsen (miR-29 mimic) has been used to treat scars and has proven safe in clinical trials when injected [7].
• Prototypes based on miR-146a are being developed to reduce inflammation in acne but have not yet undergone clinical trials.
• Due to advances in delivery technologies and decreasing production costs, topical products based on miRNAs are expected to emerge in the coming years.

Conclusion

MicroRNA therapy offers a unique opportunity to target the pathophysiologic processes of acne. Although no drugs are available on the market yet, research studies demonstrate the significant potential of these technologies to develop topical agents capable of reducing inflammation and accelerating skin healing [8].

References

1. Kulkarni J.A., Witzigmann D., Thomson S.B. et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. 2021; 16(6): 630–643.
2. Dreno B. What is new in the pathophysiology of acne, an overview. J Eur Acad Dermatol Venereol. 2017; 31(31 Suppl 5): 8–12.
3. Zeng R., Xu H., Liu Y. et al. miR-146a inhibits biofilm-derived Cutibacterium acnes-induced inflammatory reactions in human keratinocytes. J Invest Dermatol. 2019; 139(12): 2488–2496.
4. Guinea-Viniegra J., Jiménez M., Schonthaler H.B. et al. Targeting miR-21 to treat psoriasis. Sci Transl Med. 2014; 6(225): 225re1.
5. de Kerckhove M., Tanaka K., Umehara T. et al. Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds. EMBO Mol Med. 2018; 10(10): e9024.
6. He Y., Jiang X., Chen J. The role of miR-150 in normal and malignant hematopoiesis. Oncogene. 2014; 33(30): 3887–3393.
7. Mandal A., Kumbhojkar N., Reilly C. et al. Treatment of psoriasis with NFKBIZ siRNA using topical ionic liquid formulations. Sci Adv. 2020; 6(30): eabb6049.
8. Gordon S., Layton A.M., Fawcett S., Ross K. A microRNA focus on acne. Dermatol Reports. 2024; 16(2): 9902.