Retinoids remain a “gold standard” in dermatology and aesthetic skin care because they can modulate keratinocyte proliferation and differentiation, shape inflammatory pathways, and support barrier function. In practice, however, outcomes are often limited by adverse effects (retinoid dermatitis) and by substantial inter‑individual variability in response. A 2025 review in Cells proposes looking beyond traditional dosing logic and treating retinoid therapy as a multi‑layer system in which clinical results depend not only on concentration, but also on receptor selectivity, local metabolism, and the skin microbiome [1].

What the authors did

The authors compiled a broad literature review, drawing on scientific publications and clinical trial registries from recent years (with an emphasis on 2020–2025). They focused on emerging retinoid molecules, mechanisms of retinoic acid breakdown in tissues, the microbiome’s role in retinoid metabolism, and formulation technologies designed to improve stability and tolerability.

Receptor selectivity and resistance: why “precision” matters

Classic retinoids (e.g., tretinoin and isotretinoin) are not receptor‑selective and can influence multiple retinoic acid receptor subtypes (RAR‑α, RAR‑β, and RAR‑γ). Because RAR‑γ predominates in the epidermis, broader activation of other subtypes is often viewed as “extra signaling” that may contribute to irritation, erythema, and barrier disruption.

The review highlights fourth‑generation retinoids such as trifarotene, which shows high specificity for RAR‑γ. Conceptually, this may concentrate the desired epidermal effects while reducing off‑target receptor engagement, potentially improving tolerability. Another direction is targeting local retinoic acid metabolism via the CYP26 enzyme family (CYP26A1, CYP26B1, CYP26C1), which degrades retinoic acid in skin. If CYP26 activity is high, retinoic acid may be cleared too quickly, contributing to retinoid “resistance.” CYP26 inhibitors (for example, DX314 or other RAMBAs) aim to slow retinoic acid breakdown and support higher local levels of endogenous retinoic acid.

The microbiome as an active metabolic player

One of the most practice‑relevant ideas in the review is that the skin microbiome may be more than a bystander. Certain microbes can potentially shape local retinoid availability:

• Cutibacterium acnes: computational modeling suggests that some strains may be able to produce retinoic acid from carotenoids within the follicular environment, where conditions can be favorable (lipid‑rich, relatively low oxygen).
• Staphylococcus epidermidis and Corynebacterium spp.: may express enzymes that convert retinoic acid back to retinol, creating a potential “microbial sink” that could reduce signaling.

Clinical observations also suggest that isotretinoin response is associated not only with reduced C. acnes abundance, but with a shift in strain composition: improvement has been linked to a decrease in inflammation‑associated RT5 strains and a relative increase in RT2 and RT6 strains. This supports the idea that C. acnes strain profiles could become a future biomarker for retinoid response—although this concept still needs validation before routine use.

Delivery innovations: stability and comfort

Because retinoids are prone to degradation and often cause stinging or burning, the review places strong emphasis on advanced delivery approaches:

1. Nanostructured lipid carriers (NLCs): a second‑generation lipid nanoparticle platform. Unlike solid lipid nanoparticles, NLCs combine solid lipids (e.g., glyceryl distearate or cetyl palmitate) with liquid lipids/oils (e.g., oleic acid or medium‑chain triglycerides). This mixed matrix can improve drug loading and reduce expulsion during storage. The lipid structure can protect retinoids from oxidation and provide more gradual release, lowering peak exposure at the skin surface and partially supporting barrier function. In turn, stinging and erythema may be less pronounced than with conventional creams.
2. Stimulus‑responsive gels: designed to release active ingredients in response to changes in pH or temperature, helping avoid abrupt “bursts” and reducing irritation risk.
3. Depot concepts and photostabilization: hybrid nanoparticles (e.g., phospholipid/zein systems) may protect retinoids from light‑induced degradation and extend functional activity.

Clinical interpretation: examples of “precision retinoid therapy”

For skincare practitioners, the key message is that “retinoid response” is a multi‑variable equation. The concept of precision retinoid therapy is already taking shape in specific molecules and formulation strategies:

• Trifarotene: receptor‑level selectivity (RAR‑γ) aimed at focusing epidermal effects and improving tolerability in acne management.
• DX314 and other RAMBAs (retinoic acid metabolism blocking agents): compounds that are not classic retinoids; they aim to inhibit CYP26 enzymes and slow retinoic acid breakdown, supporting endogenous retinoic acid action without increasing exogenous dosing.
• NLC‑tretinoin: formulation‑level “precision,” delivering tretinoin more gradually and locally, with a less aggressive impact on the stratum corneum compared with traditional vehicles.

If a patient does not tolerate therapy well or does not see meaningful improvement, the reason may be biological rather than behavioral. High CYP26 activity may clear retinoic acid too quickly to trigger the desired cascade. Microbial context may also matter: organisms with higher potential to reduce retinoic acid to retinol could decrease local signaling, while a dominance of inflammation‑associated C. acnes strains may amplify irritation. In such cases, switching to RAR‑γ–selective molecules or to modern NLC formulations can be a rational strategy for patients with sensitive, barrier‑compromised skin.

How to explain this to a patient

A useful frame is that retinoids do not work “like a peel.” They act as regulators that gradually change how skin behaves—supporting more orderly renewal, modulating inflammation, and influencing barrier dynamics. This is why retinoids are used when the goal is not simply to “dry out” breakouts, but to reshape acne‑prone or photoaged skin over time.

Early irritation does not automatically mean the product “does not suit you.” Patients can be told: “Retinoids initiate a remodeling process. In the first weeks, dryness and redness can occur because the skin is adjusting and sensitivity pathways can be triggered.” Next‑generation molecules and delivery systems are designed to reduce this “cost” while preserving benefits.

It also helps to explain “precision” in plain language: clinicians choose not only a percentage, but also how targeted the molecule is and how it is delivered. Trifarotene is designed to act primarily where epidermal receptors are most relevant. NLC vehicles can make skin exposure more gradual and less irritating. Finally, response can vary between individuals not only due to adherence, but also due to differences in local metabolism and the follicular microbiome. In short: retinoid therapy is a biological adaptation process—not just a cosmetic routine.

Conclusion

We are entering an era of “precision retinoid therapy.” Understanding how retinoids interact with receptors, metabolic enzymes, and the microbiome supports the development of more predictable and better‑tolerated approaches. At the same time, broader clinical translation requires more comparative trials and stronger long‑term safety datasets. For now, formulation choice and careful barrier‑focused counseling remain central to successful retinoid use [1].

References

1. Łuczak J.W., Palusińska M., Maślińska-Gromadka K. et al. The next generation of skin care: transforming retinoid therapeutics. Cells 2025; 14(21): 1650. https://doi.org/10.3390/cells14211650