Topical Retinoids for Acne and Scarring: Newer Formulations Expand Multimodal Options

Decades after tretinoin was first approved for acne, a new generation of topical retinoid formulations, combined with procedural interventions and other agents, is reshaping how clinicians approach both active disease and its long-term sequelae.

A narrative review published in Pharmaceuticals synthesized evidence across clinical and experimental studies evaluating 4 topical retinoids—tretinoin, adapalene, tazarotene, and trifarotene—in the treatment of acne vulgaris and acne scarring.¹ The review, conducted by researchers at Wroclaw Medical University in Poland, examined both monotherapy and combination strategies, with emphasis on emerging drug delivery technologies and procedural adjuncts.

Why a New Look at a Decades-Old Drug Class Was Warranted

Topical retinoids have anchored acne treatment since tretinoin's approval in 1971. Despite their long track record, the field has evolved considerably: newer molecules with greater receptor selectivity, advanced delivery vehicles designed to reduce irritation, and the growing burden of acne scarring have collectively made a comprehensive synthesis of the literature both timely and clinically relevant. Acne scarring—predominantly atrophic—results from dysregulated collagen production during the inflammatory cascade that characterizes moderate and severe disease and represents one of the most persistent complications facing patients with acne.

Current American Academy of Dermatology (AAD) guidelines recommend topical retinoids at every stage of acne severity in patients aged 9 years and older, including adults and preadolescents, and support fixed-dose combinations with benzoyl peroxide or antibiotics as having strong recommendation power. Yet many clinicians remain unfamiliar with the mechanistic distinctions among retinoid generations or the degree to which novel formulations may alter tolerability and adherence.

The scale of the problem underscores why optimizing retinoid therapy matters. Acne vulgaris affects nearly 50 million people in the United States and ranks as the eighth most prevalent disease globally, according to a 2025 commentary published in Dermatology and Therapy.² That analysis, which focused on trifarotene and other retinoids across all Fitzpatrick phototypes, also reported data from the START study (NCT04856904), a large-scale, randomized, blinded phase 4 trial—finding that patients treated with trifarotene cream 0.005% achieved a 55.2% reduction in total atrophic acne scar count at week 24, compared with 29.9% in the vehicle group, with statistical significance established as early as week 2 (P = .001). The authors of that commentary recommended that topical retinoids be introduced as first-line therapy for both acne and its sequelae, with particular urgency for patients with darker Fitzpatrick phototypes or those at elevated risk of atrophic scarring.

Tolerability Profiles Distinguish Retinoid Generations

The review described 4 generations of topical retinoids with progressively greater receptor selectivity. Tretinoin, a first-generation agent and naturally occurring all-trans retinoic acid, activates all 3 retinoic acid receptor (RAR) subtypes—α, β, and γ—and carries the highest irritation potential among topical retinoids. Third-generation agents adapalene and tazarotene target RAR-β and RAR-γ with greater selectivity; adapalene demonstrates low to moderate irritation potential, while tazarotene's high receptor affinity confers high potency alongside a higher risk of irritant dermatitis. Trifarotene, the sole fourth-generation agent approved in 2019, offers highly selective RAR-γ activation, resulting in a moderate irritation profile and favorable safety for use over larger body surface areas, including truncal acne.

One comparative irritancy study cited in the review established a clear hierarchy: adapalene 0.1% cream showed the lowest irritation potential, followed by adapalene 0.1% gel, tazarotene 0.05% cream, and tazarotene 0.1% cream. A separate head-to-head study found that tazarotene 0.045% lotion, formulated using polymeric emulsion technology, demonstrated lower irritation than adapalene 0.3% gel and trifarotene 0.005% cream in patch testing.

Novel Delivery Technologies Improve Stability and Skin Penetration

A substantial portion of the review addressed advances in drug delivery, noting that formulation innovation has become a primary lever for improving both tolerability and clinical outcomes. Tretinoin's chemical instability, particularly its susceptibility to oxidative degradation when combined with benzoyl peroxide in the liquid phase, had long been a barrier to fixed-dose combination therapy. Microencapsulation technology, in which both tretinoin and benzoyl peroxide are individually encapsulated via a sol-gel process, resolved this incompatibility and enabled a commercially available combination product.

Nanostructured lipid carriers (NLCs) were evaluated for both tretinoin and adapalene. In 1 double-blind, split-face randomized trial in patients with acne vulgaris, a 0.05% NLC-tretinoin formulation produced significantly greater reductions in noninflammatory lesions than a conventional 0.05% tretinoin cream, along with higher patient satisfaction scores; however, the study was limited by a small sample size. Microsponge hydrogel and niosome-based adapalene formulations also demonstrated promising stability, controlled release, and tolerability in early-stage studies.

Scar Treatment Evidence Builds Across Retinoid Classes

The review also examined the growing body of evidence supporting topical retinoids in acne scar management. Tretinoin's stimulation of collagen I and III synthesis and its ability to improve newly formed collagen bundle organization supported its historic use in both atrophic and hypertrophic scarring. A complex protocol incorporating tretinoin 0.05% cream as a conditioning agent—followed by subcision, microneedling, and trichloroacetic acid (TCA) peeling in alternating sessions—produced high patient satisfaction scores even in individuals with grade 3 and 4 scars and was considered appropriate for higher skin phototypes.

For trifarotene, a phase 4 controlled study enrolling more than 100 patients found a significant reduction in acne scarring over 24 weeks compared with placebo. A separate case series described sequential use of trifarotene followed by non-animal-stabilized hyaluronic acid (NASHA) gel administered in 3 to 10 sessions, with the authors attributing meaningful clinical improvement to synergistic collagen remodeling effects.

The authors noted that adapalene 0.3% demonstrated scar texture improvement of 1 to 2 grades from baseline in 55.6% of patients across a 24-week maintenance study, while a separate trial found that both the adapalene/benzoyl peroxide combination and benzoyl peroxide monotherapy reduced scar progression compared with placebo, suggesting that anti-inflammatory effects of benzoyl peroxide may independently contribute to scar prevention.

Combination Strategies Support Antibiotic Stewardship

The triple-combination formulation of adapalene 0.15%, benzoyl peroxide 3.1%, and clindamycin phosphate 1.2% was highlighted as the only commercially available option combining all 3 drug classes in a single product. A 24-week analysis of Cutibacterium acnes susceptibility in patients using this formulation found good effectiveness, tolerability, and no evidence of developing bacterial resistance, a finding relevant to ongoing antibiotic stewardship efforts in dermatology. The AAD guidelines note that topical antibiotics should not be used as monotherapy and that benzoyl peroxide should be added to retinoid-antibiotic regimens to reduce resistance risk.

Study Limitations and Gaps in the Literature

The review's authors acknowledged that evidence supporting novel formulations frequently derives from small or heterogeneous patient populations, with some technologies evaluated only at the preclinical or animal-model stage. Human data for several NLC, microemulsion, and niosome-based formulations remained limited at the time of review, and the authors noted that no studies to date have evaluated the combination of trifarotene with benzoyl peroxide or clindamycin. The literature on combining topical retinoids with procedural technologies such as fractional carbon dioxide laser was described as particularly sparse.

As the authors wrote, "topical retinoids represent a relevant therapeutic option in acne vulgaris and acne scarring, from monotherapy in mild cases to components of multimodal treatment protocols in more severe disease"—a conclusion that underscores the breadth of the drug class while reinforcing the need for individualized, evidence-based prescribing decisions.

Further large-scale, comparative studies using well-defined patient populations are needed to clarify optimal clinical positioning for advanced delivery systems and to establish which multimodal protocols offer the greatest benefit across acne severity levels and skin phototypes.

References

1. Tobiasz A, Jankowska-Konsur A, Nowicka D. Topical retinoids in acne vulgaris and acne scars—from monotherapy to combining regimens. Pharmaceuticals. 2026;19(4):620. doi:10.3390/ph19040620
2. Issa N, Alexis A, Baldwin H, et al. Recommendations to improve outcomes in acne and acne sequelae: a focus on trifarotene and other retinoids. Dermatol Ther (Heidelb). 2025;15(3):563-577. doi:10.1007/s13555-025-01344-y