Biological Photoprotection: A Review of its Mechanisms, Evidence, and Clinical Implications

Abstract

Biological photoprotection refers to the enhancement, preservation, or mimicry of the skin’s intrinsic defense systems to prevent or mitigate damage induced by solar and environmental stressors. Unlike conventional sunscreens, which primarily act by reducing photon penetration, biological photoprotection targets the downstream molecular and cellular responses triggered by these exposures. It is achieved by incorporating nonfiltering photoprotective ingredients (PINGs) into sunscreens, which act on key biological pathways involved in skin damage and recovery. Emerging evidence suggests that these ingredients may provide additive protection when combined with ultraviolet (UV) filters, particularly in mitigating oxidative damage, supporting DNA repair, and modulating inflammatory and pigmentary responses. However, the current evidence base remains limited, with many studies characterized by small sample sizes, short durations, and heterogeneous methodologies. Taken together, biological photoprotection represents a complementary, but still evolving, dimension of modern photoprotection. Further research is required to establish standardized evaluation methods and to determine its clinical relevance under real-world conditions.

Plain Language Summary

Sunlight does more than cause sunburn. It can trigger harmful changes in the skin, including damage to cells, inflammation, changes in skin color, and faster skin aging. Traditional sunscreens mainly work by blocking or absorbing ultraviolet (UV) rays before they enter the skin. However, they do not fully protect against all the ways sunlight and the environment can damage the skin. Biological photoprotection is an approach that helps support the skin’s natural defenses. It involves adding ingredients to sunscreens that help the skin protect and repair itself. These ingredients can help reduce damage, support the skin’s repair processes, calm inflammation, and help control changes in skin color. Research suggests that these ingredients can provide extra protection when used together with UV filters. However, most studies so far have been small and short-term, so more research is needed to understand how well they work in everyday use. For now, biological photoprotection should be seen as an addition to, not a replacement for, traditional sun protection methods such as using sunscreen, seeking shade, and wearing protective clothing.

Key Summary Points

Biological photoprotection extends beyond UV filtration by supporting the skin’s intrinsic antioxidant, DNA-repair, and immunomodulatory defenses against solar and environmental stressors.

This approach is intended to complement, rather than replace, conventional UV filters, targeting oxidative, inflammatory, and genomic pathways that are not fully addressed by filters alone.

Emerging clinical and experimental evidence suggests that topical nonfiltering photoprotective ingredients (PINGs) may reduce oxidative stress, DNA damage, inflammation, and pigmentation; however, much of the current evidence is derived from relatively small, short-term studies using surrogate endpoints.

There is currently a lack of harmonized methodologies and standardized metrics to evaluate biological photoprotection, which limits comparability across studies and products.

Integrating biological and filter-based approaches may offer a more comprehensive strategy for photoprotection; however, further robust clinical validation is needed before its widespread adoption.

Introduction

Sun-induced skin damage remains a major public health concern worldwide, contributing to sunburn, photoaging, pigmentary disorders, photodermatoses, and photocarcinogenesis. Conventional photoprotection strategies, based on organic and inorganic ultraviolet (UV) filters, have been highly effective in reducing acute photodamage, such as erythema and DNA lesions, caused by ultraviolet B (UVB) radiation. However, these filters primarily act as physical or chemical barriers, attenuating photon penetration rather than addressing the biological processes triggered by solar and environmental exposure. Consequently, despite widespread sunscreen use, signs of chronic photoaging and UV-related disease persist globally [1].

A growing body of evidence demonstrates that skin damage induced by solar radiation extends beyond the protection provided by most conventional filters. Other wavelengths of sunlight, including long-wavelength UVA1, visible light (VL), and infrared (IR) radiation, penetrate deeply into the skin and trigger oxidative stress, inflammation, and mitochondrial dysfunction [2]. These insults activate signaling pathways which drive matrix degradation, pigment dysregulation, and immune modulation. Moreover, exposome factors, including air pollution, temperature fluctuations, humidity, tobacco smoke, dietary patterns, insufficient sleep, and psychosocial stress, act synergistically with light exposure to amplify reactive oxygen species (ROS) generation and accelerate extrinsic skin aging [2, 3]. Traditional UV filters alone cannot counter these downstream biological effects.

In response, the concept of biological photoprotection has emerged as a complementary strategy to traditional filter-based approaches [4, 5]. Biological photoprotection is an approach that supports the skin’s intrinsic defense and repair mechanisms against damage induced by solar and other environmental stressors. Rather than simply blocking photons, this paradigm seeks to reinforce the skin’s innate capacity to resist, repair, and recover from photodamage.

It is achieved by incorporating nonfiltering photoprotective ingredients (PINGs) into sunscreens, which act on key biological pathways involved in skin damage and recovery. Several molecular mechanisms contribute to biological photoprotection (Fig. 1) [4, 5]. Antioxidants neutralize ROS and maintain redox homeostasis. DNA-repair enzymes correct mutagenic lesions such as cyclobutane pyrimidine dimers (CPDs). Immune modulators preserve antigen presentation and prevent photoimmunosuppression, while anti-inflammatory substances restore immune balance. Together, these mechanisms form a biological shield that complements the optical barrier provided by UV filters.

Fig. 1.

Mechanistic classification of nonfiltering photoprotective ingredients (PINGs). PINGs are categorized according to their primary biological mechanisms of action, including antioxidant activity, DNA repair, anti-inflammatory effects, pigmentation regulation, and immunomodulation

Sunscreens that integrate antioxidants, DNA-repair enzymes, peptides, osmolytes, and other biologically active ingredients capable of supporting intrinsic defense mechanisms represent an emerging evolution in photoprotection, one that extends protection beyond UV filtration toward cellular resilience, genomic stability, and long-term skin health.

This review outlines the principles and mechanisms underlying biological photoprotection and synthesizes current evidence regarding its clinical relevance. It presents a conceptual framework for evaluating biologically driven efficacy, within which topically applied PINGs represent one important means of reinforcing intrinsic cutaneous defense systems [4, 5]. In doing so, it aims to contribute to a more integrated, mechanism-based understanding of photoprotection that encompasses both optical filtering and biological defense.

Methods

Literature Review

The objective of this review was to synthesize current knowledge and explore key mechanistic, clinical, and methodological considerations relevant to biological photoprotection.

A structured narrative review of the literature was conducted to summarize current evidence relating to biological photoprotection. Relevant publications were identified through searches of PubMed, Scopus, and Web of Science using combinations of terms including “biological photoprotection”, “oxidative stress”, “DNA repair”, “photoimmunosuppression”, “ultraviolet”, “visible light”, “infrared radiation”, and “nonfiltering photoprotection”. The search included studies published up to the end of June 2025 and was limited to articles published in English with full text availability. Reference lists of relevant review articles and primary studies were also screened to identify additional publications.

Titles and abstracts were screened for relevance, and full-text articles were assessed where appropriate, with a particular focus on biological responses of the skin to UV, VL, IR, and environmental stressors. Original experimental studies were prioritized for evidence synthesis, while review articles were used for contextual background and identification of additional references. Human in vivo studies were prioritized where available, alongside relevant ex vivo and mechanistic in vitro studies. Studies limited solely to optical filter performance or cosmetic characteristics were not considered unless they included biologically relevant endpoints.

Given the narrative nature of this review, no formal systematic review protocol or quantitative meta-analysis was performed. However, studies were qualitatively assessed on the basis of study type, relevance of biological endpoints, and consistency of findings across the literature as described previously [4].

As with all narrative reviews, potential publication and selection biases cannot be excluded, and the synthesis reflects the available literature and its interpretation within the context of biological photoprotection.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals.

The Impact of the Exposome on Human Skin

Human skin is continuously exposed to an array of environmental and lifestyle stressors, including solar radiation, air pollution, temperature, humidity, nutrition, psychological stress, lack of sleep, tobacco use, and chemical exposures, collectively termed the skin exposome [2, 3]. Among these, solar radiation, air pollution, and environmental conditions, such as heat and humidity, are particularly relevant targets for biological photoprotection.

Solar Radiation

Solar radiation comprises UV, VL, and IR wavelengths, each of which induces distinct biological responses in the skin.

UVB (280–320 nm) primarily affects the epidermis, causing direct DNA photolesions, such as CPDs and (6–4) photoproducts, leading to mutations in tumor suppressor genes and activation of inflammatory cascades [6].

UVA (320–400 nm), accounting for over 90% of terrestrial UV, penetrates the dermis, generating ROS that damage nuclear and mitochondrial DNA (mtDNA), lipids, and proteins indirectly. It also activates key transcription factors, most notably AP-1 and MAPKs, that upregulate matrix metalloproteinases (MMPs), accelerating collagen degradation and impairing dermal structure [7]. In parallel, these pathways suppress new collagen synthesis and trigger a sustained inflammatory response, further contributing to dermal thinning, loss of elasticity, and visible photoaging.

VL, particularly high-energy visible light (HEVL; 400–500 nm), triggers ROS production in mitochondria and induces sustained melanogenesis via Opsin 3 activation in melanocytes, producing long-lasting pigmentation in darker phototypes [8–11].

IR-A (700–1400 nm) penetrates deeply into the dermis, generating mitochondrial ROS and heat-induced signaling that accelerates collagen breakdown [12, 13].

These overlapping mechanisms reveal that photodamage extends well beyond UV wavelengths, reinforcing the need for protection strategies that target molecular and cellular defense systems.

Pollution, Heat, and Humidity

Airborne pollutants, such as polycyclic aromatic hydrocarbons, particulate matter, and ozone, bind to aryl hydrocarbon receptors (AhR), initiating oxidative and inflammatory cascades that exacerbate pigmentary and aging phenotypes [14–16].

Heat and humidity further amplify ROS production, increasing dermal matrix degradation and pigmentation [17, 18]. Together, these nonradiative exposome factors interact synergistically with solar radiation, underscoring the biological impact of photodamage [19].

Limitations of Conventional Filter-Based Photoprotection

Despite their proven efficacy in preventing erythema and sunburn, conventional sunscreens, composed of organic and inorganic UV filters, offer an incomplete solution to the biological complexity of solar and environmental skin damage. These filters function by absorbing, reflecting, or scattering UV photons, thereby reducing the radiant dose that reaches the skin. However, their photophysical action does not address the cascade of oxidative, inflammatory, and immunologic events triggered within the skin even under suberythemal exposure conditions [20, 21].

Incomplete Spectral Coverage

Most currently approved UV filters are optimized for the UVB and short-UVA ranges (280–340 nm), leaving long-wavelength UVA1 (340–400 nm), VL (400–700 nm), and IR-A (700–1400 nm) largely unmitigated. This limitation is particularly evident in the USA, where only 17 UV filters are authorized, compared with 29 in the European Union, where next-generation molecules, such as Phenylene bis-diphenyl triazine and Methoxypropylamino cyclohexenylidene ethoxyethylcyanoacetate, extend protection further into the long-UVA1 and HEVL regions [22–25]. Although iron oxide pigments can attenuate VL through scattering, their cosmetic drawbacks and restricted tonal suitability limit widespread adoption [5, 26].

Neglect of Biological Damage Mechanisms

Even when high sun protection factor (SPF) and UVA-PF levels are achieved, optical filtration alone cannot prevent biochemical and cellular damage such as DNA lesions, oxidative stress, immunosuppression, or disruption of the skin barrier [20, 21]. Suberythemal UV doses continue to induce CPDs, alter cytokine profiles, and impair Langerhans-cell function [21]. Exposure to UVA also contributes to the formation of “dark-CPDs,” which continue to arise hours after exposure through melanin-mediated chemiexcitation [27], adding to the mutagenic burden even in the absence of ongoing UV exposure. These effects help explain why photoaging and photocarcinogenesis persist despite regular sunscreen use.

Inadequate Real-World Application

Under everyday conditions, users typically apply less than half the recommended dose of 2 mg/cm² and rarely reapply at appropriate intervals. This results in an effective SPF reduction of 50–80%, leaving skin underprotected even against the UV spectrum that filters are designed to block. The real-life efficacy of sunscreen is therefore far below its laboratory-measured potential [1]. Moreover, most individuals do not use sunscreen indoors, despite continuous exposure to UVA, VL, and IR that penetrate window glass and contribute to photoaging and pigmentation [28].

Lack of Protection Against Exposome Stressors

Modern environmental exposures, including air pollution, temperature extremes, and humidity fluctuations, act synergistically with solar radiation to accelerate oxidative and inflammatory damage [19]. Current filters offer no defense against these nonradiative stressors, which contribute to pigmentary disorders and premature skin aging through AhR activation, lipid peroxidation, and extracellular matrix degradation.

Environmental and Cosmetic Challenges

Growing awareness of ecotoxicological concerns, particularly the impact of certain organic filters on marine ecosystems, has led to restrictions on ingredients such as oxybenzone, octinoxate and octocrylene [29, 30]. In addition, issues of cosmetic acceptability (residue, color mismatch, sensory feel) may influence real-world use, especially in individuals with skin of color or oily skin [1].

Biological Photoprotection

These intrinsic and practical limitations underscore that photoprotection cannot rely solely on optical filtration. Recognizing these unmet needs, early work by Jean Krutmann and colleagues in the 2000s demonstrated that supplementing traditional filters with the DNA-repair enzyme photolyase could enhance the skin’s capacity to correct UV-induced lesions [31]. Since then, the concept has evolved to encompass a range of mechanism-driven actives (antioxidants, DNA-repair enzymes, osmolytes, and immunomodulators) that strengthen biological resilience to solar and exposome stress. These ingredients, termed PINGs, are designed to complement rather than replace UV filters by addressing the underlying biological consequences of light and environmental exposure [4, 5].

Definition of Biological Photoprotection

Biological photoprotection refers to the enhancement, preservation, or mimicry of the skin’s intrinsic defense systems to prevent or mitigate damage induced by solar and environmental stressors. Unlike conventional UV filters, which function primarily by absorbing, reflecting, or scattering radiation, biological photoprotection involves reinforcement of cellular and molecular mechanisms that contribute to the maintenance of cutaneous homeostasis under exposure to UV, VL, IR, and pollution-related stressors.

Within the scope of this review, the term is used to describe strategies centered on topically applied PINGs that support antioxidant capacity, DNA repair processes, immune resilience, and modulation of inflammatory pathways. While other approaches to photoprotection, including oral or systemic strategies, are recognized within the broader field, they are not the primary focus of the present discussion.

Mechanism of Action of PINGs

PINGs can be broadly grouped into six mechanistic categories, reflecting the principal biological targets involved in skin defense (Fig. 1). This framework, originally proposed by Brown and Krutmann [4, 5], provides a useful foundation for classifying photoprotective ingredients according to their mechanisms of action (Table 1). Together, these pathways define the biological foundation that complements UV filters.

Table 1.

Classification of PINGs by their mechanism of action (MoA)

MoA category	Primary target	Principal PING(s)
1. Antioxidant/ROS scavenging	Neutralizing free radicals (singlet oxygen, superoxide) Activate NRF2 to upregulate intrinsic antioxidant enzymes	L-Ascorbic acid (Vitamin C) (●●●●○), α-Tocopherol (Vitamin E) (●●●●○), Tocopheryl acetate (●●●●○), Melatonin (●●●○○), N-acetyl-L-cysteine (●●●○○)
2. Compatible solutes	Stabilizing cellular structures by forming protective hydration shells around proteins, DNA, and lipids	Ectoine (●●●○○), mannitol (●●●○○), betaine (●○○○○)
3. DNA repair	Promoting excision and repair of photoproducts (e.g., CPDs)	Photolyase (●●●●○), T4 Endonuclease (●●●○○), SIK inhibitors (●●○○○)
4. Immunomodulation	DNA repair; inhibition of immunomodulatory cytokine release	Nicotinamide (●●●●○), Green tea extract (●●●○○)
5. Anti-inflammatory	Inhibition of NF-κB signaling; inhibition of UV-induced inflammatory cytokine release; inhibition of NOS	Epigallocatechin gallate (EGCG) (●●●○○)
6. Pigmentation modulation	Regulating melanogenesis	Isobutylamido thiazolyl resorcinol (●●●●○), 2-mercaptonicotinoyl glycine (●●●○○), p-coumaric acid (●●●○○)

Evidence strength is represented using a 5-point visual scale (●), based on the level and consistency of clinical evidence: ●●●●● = Very strong (multiple randomized clinical studies and consistent in vivo evidence). ●●●●○ = Strong (controlled human studies with supportive mechanistic data). ●●●○○ = Moderate (limited clinical evidence). ●●○○○ = Limited (primarily preclinical or inconsistent evidence). ●○○○○ = Preliminary (mechanistic or exploratory data only)

CPD cyclobutane pyrimidine dimer, NF-κB nuclear factor kappa-B, NOS nitric oxide synthase, SIK salt-inducible kinase

Evidence Supporting Biological Photoprotection in Clinical Settings

Controlled clinical studies demonstrate that reinforcing biological defense pathways enhances skin protection beyond that provided by UV filters alone. Trials evaluating antioxidants, DNA-repair enzymes, and osmolytes consistently show reductions in oxidative stress, DNA damage, inflammatory mediators, and pigmentation following controlled radiation exposure. Selected evidence is presented in Table 2.

Table 2.

Clinical studies of sunscreens incorporating photoprotective ingredients (PINGs)

Sunscreen	Principal PING(s)	Study design	Key findings	Reference
SPF50	Diethylhexyl syringylidene malonate, vitamin E, ascorbyl palmitate, licochalcone A, glycyrrhetinic acid (antioxidant PINGs)	Prospective, controlled clinical study; n = 10 (9 completed; all female, Fitzpatrick IV–VI); five test sites on back treated with SPF 50 ± antioxidants or tinted SPF 20 control; single VL + UVA1 (370–700 nm, 380 J/cm2) exposure; clinical photography, IGA scoring, and DRS at 0, 24 h, 7 days	5-AO blend SPF 50 significantly reduced visible-light and UVA1-induced pigmentation and erythema versus SPF without AO (p < 0.05), achieving protection comparable to tinted sunscreen while avoiding cosmetic coloration	Ruvolo et al. [42]
SPF25	Caffeine, vitamin E, vitamin C (aminopropyl ascorbyl phosphate), echinacea pallida extract, gorgonian extract, and chamomile essential oil (Antioxidant PINGs)	Prospective, controlled in vivo human study; n = 5 (18–40 y; mean 25; Fitzpatrick I–III, mainly II). Two SPF-25 formulations (with and without antioxidants) applied 2 mg/cm2 to buttock skin 15 min before solar-simulated UVR (2 × MED, 290–400 nm); biopsies 48 h later for CD1a and MMP-1 immunohistochemistry	SPF 25 + AOX reduced UV-induced MMP-1 expression by 60% versus 43% with SPF alone (p < 0.05) and prevented Langerhans-cell loss (4% versus 35% reduction in untreated skin)	Matsui [43]
SPF 25	Caffeine, vitamin E, vitamin C (aminopropyl ascorbyl phosphate), echinacea pallida extract, gorgonian extract, and chamomile essential oil (antioxidant PINGs)	Randomized controlled in vivo clinical study; n = 40 healthy women (20–45 y; Fitzpatrick III–IV). Seven test sites on lower back exposed to solar-simulated UVR (1.5 × MED) for 4 days. Treatments: vehicle, SPF 25 alone, AOX alone, or SPF 25 + AOX. Biopsies 72 h post-exposure for histology and immunohistochemistry	Compared with SPF 25 alone, SPF 25 + AOX reduced melanin formation by 70% (versus 60%, p = 0.05), completely prevented MMP-9 induction, and better-preserved Langerhans cells. AOX alone reduced pigmentation 30% and prevented epidermal thickening (−40% versus control)	Wu [44]
SPF 30	Vitamin E, vitamin C, ubiquinone, grape-seed extract (antioxidant PINGs)	Randomized, double-blind, vehicle-controlled clinical study; n = 30 healthy adults (11 M, 19 F; mean age ≈ 48 y). Two 3 × 3 cm buttock sites treated for 10 days with SPF 30 ± AO cocktail (2 mg/cm2); single IR-A exposure (360 J/cm2; 760–1440 nm); 24 h biopsies analyzed for MMP-1 mRNA expression	SPF 30 + AO significantly reduced IR-A-induced MMP-1 mRNA upregulation (p < 0.05) versus untreated and SPF-only sites; SPF alone showed no significant protection. Antioxidants were required for effective IR-A photoprotection	Grether-Beck et al. [45]
SPF 30	Ectoine + mannitol (Osmolyte PINGs)	Open, intra-individual, investigator-approved clinical study; n = 10 men aged 20–44 years (Fitzpatrick II–III) with oily skin on the back. Four test areas received vehicle or active formulation (0.1% ectoine + 0.1% mannitol) ± UV filters for 3 days; 2 MED UVA + UVB irradiation at D3; biomarker sampling at D4	Active formulation significantly protected skin lipids and enzymes after UV exposure: squalene oxidation ↓ 58%, catalase activity ↑ 60%, and trans-urocanic acid isomerization ↓ 14% versus irradiated control (all p < 0.01). Combined with UV filters, protection rose to 77–84% for squalene and catalase (synergistic CDI = 0.9)	Fontbonne et al. [46]
SPF 50	Photolyase (Anacystis nidulans) (DNA repair PING)	Randomized, controlled in vivo study; n = 10 healthy volunteers (5 M, 5 F; 25–36 y; Fitzpatrick II). Each subject received four daily solar-simulated UVR exposures (3 × MED) on marked skin sites treated with vehicle, SPF 50 alone, or SPF 50 + 1% liposomal photolyase*	Compared with SPF 50 alone, SPF 50 + photolyase reduced UV-induced CPDs by 93% (versus 62%) and apoptosis by 82% (versus 40%) (p < 0.001), demonstrating superior DNA-damage repair and anti-apoptotic protection	Berardesca et al. [47]
SPF 50	Photolyase (Anacystis nidulans) + endonuclease (Micrococcus luteus) (DNA repair PINGs)	Prospective, intra-individual pilot clinical study; n = 12 healthy white adults (6F/6 M; Fitz I–II). Six 10-mm back sites per subject: untreated; UVR only; vehicle + UVR; SPF50 + UVR; SPF50 + endonuclease + UVR; SPF50 + photolyase + endonuclease + UVR. 3 × MED solar-simulated UVR on 4 consecutive days; biopsies 24 h after final exposure	SPF50 alone: modest attenuation of telomere loss and c-FOS upregulation. SPF50 + endonuclease: greater protection versus SPF alone. SPF50 + photolyase (pre-irradiation) + endonuclease (post-irradiation): complete abrogation of UV-induced telomere shortening and c-FOS hyperexpression (restored to nonirradiated levels)	Emanuele et al. [48]
SPF 50 +	Sclareolide + niacinamide (anti-inflammatory and depigmenting PINGs)	Investigator-blinded, randomized, intra-individual controlled study; n = 20 (24–49 y; Fitzpatrick IV–V) with history of PIH. Six back sites (tape-stripped or intact) received UV (1.5 × MED) + VL (14 J/cm2) exposures ± sunscreen for 20 days; colorimetry (ΔITA°, ΔL*, Δa*, Δb*, ΔE) and clinical scoring through Day 36	Sunscreen significantly prevented UV/VL-induced pigmentation and erythema. ΔITA° protection: + 5.96 (stripped, p < 0.001) and + 11.76 (nonstripped, p < 0.001) versus unprotected; pigmentation ↓ 26–53%, erythema ↓ 43–94%. Colorimetric indices improved 48–87%. No adverse events. Demonstrated dual anti-inflammatory and depigmenting benefit for PIH prevention in skin of color	Passeron et al. [49]

AO antioxidant, AOX antioxidants, 5-AO five-antioxidant blend (diethylhexyl syringylidene malonate + vitamin E + ascorbyl palmitate + licochalcone A + glycyrrhetinic acid), CDI combination drug index, CD1a cluster of differentiation 1a, CPD cyclobutane pyrimidine dimer; ΔE, ΔL*, Δa*, Δb*, ΔITA°, CIELAB colorimetric parameters (total color, lightness, red–green, yellow–blue, individual typology angle), DRS diffuse reflectance spectroscopy, F female, M male, FPT Fitzpatrick phototype, IGA investigator global assessment, IL-1α interleukin-1 alpha, IR-A infrared-A radiation, MED minimal erythema dose, MMP-1/-9 matrix metalloproteinase-1/-9, NIAC niacinamide, PIH postinflammatory hyperpigmentation, PING photoprotective ingredient with nonfiltering gain, ROS reactive oxygen species, SPF sun-protection factor, ssUV/ssUVR solar-simulated ultraviolet (radiation), UVA/UVB/UVR ultraviolet A/B/radiation, VL visible light (≈ 400–700 nm)

Collectively, these findings suggest that biological reinforcement may provide additional protection when combined with filters, addressing oxidative, genetic, and immunologic endpoints not captured by SPF metrics. Much of this evidence, however, is derived from relatively small studies that are short in duration and conducted under controlled experimental conditions. As such, it may not fully reflect real-world patterns of sunscreen use and environmental exposure. It should therefore be interpreted as preliminary rather than definitive clinical validation.

Evidence Strength and Leading Candidates

Although many PINGs have been proposed, only a subset demonstrate reproducible, high-quality clinical evidence of efficacy.

PINGs with the most consistent clinical support, based on data available up to the end of 2022 [4, 5], include:

• L-ascorbic acid (vitamin C), a potent ROS scavenger that reduces oxidative stress.

• Nicotinamide (vitamin B₃), which restores cellular NAD⁺ levels, supporting DNA repair and reducing UV-induced immunosuppression.

• Tocopheryl acetate (Vitamin E), a lipid-phase antioxidant that limits erythema and lipid peroxidation.

• Isobutylamido thiazolyl resorcinol, an effective tyrosinase inhibitor for preventing post-UV hyperpigmentation.

• N-acetyl-L-cysteine, a glutathione precursor that suppresses MMP expression and protects against photoaging.

• Photolyase, a DNA-repair enzyme that decreases CPDs and UV-induced apoptosis, improving genomic stability.

• Epigallocatechin gallate (EGCG), an anti-inflammatory polyphenol that inhibits NF-κB and COX-2 signaling.

Since then, emerging evidence has highlighted several ingredients of particular interest, including:

• Salt-inducible kinase (SIK) inhibitors, which enhance post-UV DNA repair at levels comparable to photolyase [32].

• 2-mercaptonicotinoyl glycine (2-MNG), a potent inhibitor of UV- and HEVL-induced hyperpigmentation [33–35].

Scientific, Regulatory, and Formulation Challenges in Biological Photoprotection

Measuring and Standardizing Biological Photoprotection

Conventional sunscreen performance is primarily based on determining the SPF using minimal erythema dose (MED) testing [36]. While SPF provides a standardized measure of protection against UV-induced erythema, it does not capture the broader biological processes targeted by biological photoprotection, including DNA repair, oxidative stress modulation, immune preservation, and pigmentation control.

Although alternative indices have been proposed [20, 21, 37, 38], no widely accepted framework exists to quantify biological photoprotection. This lack of standardization limits comparability across studies and complicates interpretation of efficacy in relation to clinical outcomes.

Translational Challenges

Assessing biological activity in finished formulations is also inherently challenging. Many relevant endpoints rely on invasive or laboratory-based methodologies, which are not readily applicable to large-scale or real-world evaluation.

Additionally, findings from controlled or in vitro studies do not necessarily translate to efficacy in intact human skin. Factors, such as formulation characteristics, ingredient stability, skin penetration, and real-world usage patterns, influence whether biologically active compounds reach their target sites and exert measurable effects.

Regulatory Considerations

The integration of biologically active ingredients into sunscreen formulations introduces additional regulatory complexity. In the USA, sunscreens are regulated as over the counter (OTC) drugs under the Food and Drug Administration (FDA) monograph system. Within this framework, only UV filters are recognized as “active ingredients” and must be declared as such on the label. PINGs, including antioxidants or DNA-repair enzymes, are not classified as active drug ingredients unless specific therapeutic claims are made. By contrast, in the European Union and many other regions, sunscreens are regulated as cosmetic products, provided their primary intended purpose is protection against UV radiation. Ingredients that support endogenous defense mechanisms are therefore generally considered cosmetic components.

If, however, claims extend toward prevention of defined pathologies (e.g., actinic keratoses) or treatment of specific disorders (e.g., melasma), regulatory classification may shift accordingly, requiring demonstration of safety, efficacy, and compliance with more stringent manufacturing standards.

In certain high-risk populations, more stringent regulatory classification, such as registration as a medical device or drug, may be appropriate. For example, photolyase-containing formulations are regulated as medical devices in Europe, reflecting their positioning for use in in patients at increased risk of actinic keratosis [39–41].

Safety Considerations

The combination of PINGs with UV filters also raises several unresolved safety considerations. Many biologically active compounds are designed to penetrate the skin, whereas UV filters are intended to remain at the surface. Co-formulation may therefore alter the dermal absorption profile of UV filters.

Current safety assessments do not systematically address whether the inclusion of PINGs modifies the dermal absorption, photoreactivity, or toxicological profile of UV filters, and evidence on this issue remains limited. In addition, potential interactions between PINGs and UV filters, as well as cumulative effects on skin irritation or sensitization, remain insufficiently characterized.

Limitations

Despite increasing interest, the current evidence base for biological photoprotection remains limited. Most available clinical studies are small and short in duration, which restricts statistical power and limits generalizability to broader populations and long-term outcomes.

In addition, many studies rely on surrogate or intermediate endpoints, such as markers of oxidative stress, pigmentation indices, or molecular indicators of DNA damage. While these endpoints are mechanistically relevant, their relationship to clinically meaningful outcomes, including prevention of photoaging or skin cancer, remains incompletely established.

Evidence supporting protection against non-UV components of solar radiation and other exposome factors is particularly limited and often derived from in vitro or ex vivo studies rather than robust in vivo clinical trials. Furthermore, heterogeneity in formulation design, ingredient concentration, and delivery systems complicates cross-study comparison and interpretation.

These limitations underscore the need for cautious interpretation of current findings and support the positioning of biological photoprotection as a complementary, rather than substitutive, approach to established strategies.

Conclusions

Biological photoprotection represents a conceptual extension of conventional photoprotection by addressing biological responses to solar and environmental exposure. Current evidence supports its potential to complement UV filters; however, it remains largely preliminary. Accordingly, biological photoprotection should be interpreted as a promising but still evolving approach. Broader integration into clinical practice will require standardized methodologies, harmonized biological endpoints, and well-designed studies demonstrating clinically relevant benefits under real-world conditions.

Author Contributions

Anthony Brown: conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing—original draft, and writing—review and editing. Thierry Passeron: investigation, formal analysis, and writing—review and editing. Yolanda Gilaberte: investigation, formal analysis, and writing—review and editing. Jaime Piquero-Casals: investigation, formal analysis, and writing—review and editing. Sergio Schalka: investigation, formal analysis, and writing—review and editing. Carla Simonetto: project administration and writing—review and editing. Monica Foyaca: resources, project administration, and writing—review and editing. Henry W. Lim: conceptualization, formal analysis, and writing—review and editing. Jean Krutmann: conceptualization, formal analysis, and writing—review and editing.

Funding

Sponsorship for this review and Rapid Service Fee were funded by ISDIN, Spain.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Anthony Brown, Carla Simonetto, and Monica Foyaca are employees of ISDIN. Thierry Passeron has received grants and/or honoraria from AbbVie, ACM Pharma, Almirall, Amgen, Astellas, Beiersdorf, Bristol Myers Squibb, Calypso, Caudalie, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte Corporation, ISDIN, ISIS Pharma, Janssen, LEO Pharma, L’OREAL, Eli Lilly, NAOS, Novartis, Pfizer, Roivant, Sun Pharmaceuticals, SVR, Symrise, Takeda, UCB, and VYNE Therapeutics. He is the cofounder of NIKAIA Pharmaceuticals. Yolanda Gilaberte has acted as a consultant for Almirall, ISDIN, Cantabria Labs, Abbvie, Incyte, and Pfizer. Jaime Piquero-Casals is a consultant for ISDIN. Sergio Schalka has received grants and/or honoraria from Aché, Beiersdorf, Cantabria, FQM Brasil, ISDIN, L’OREAL, and NAOS. Henry W. Lim has served as investigator for Incyte, La Roche Posay, Pfizer, and PCORI; consultant for ISDIN, Beiersdorf, Ferndale, L’Oréal, Eli Lilly, Zerigo Health, Skinosive, Kenvue, Cantabria Labs, NAOS, and Boehringer Ingerheim, and speaker on general educational session for La Roche-Posay, Cantabria Labs, Pierre Fabre, NAOS, Uriage, Pfizer, ISDIN, Clinuvel, and Rxilient. Jean Krutmann serves as a consultant to / IUF obtains funding from: AbbVie, Activen, Amway, Beiersdorf, bitop, Blue Lagoon, Evonik, ISDIN, Laboratoire Native, La Roche-Posay, L’Oreal, Mary Kay, Meitu, Mistine, Mibelle, SinoCell Biotechnology, Skinceuticals, Stada, Symrise, and Vichy.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals.