Natural Photosensitizers in Cancer Therapy: A Chemo‐Biodiversity Perspective on Light‐Activated Natural Compounds

ABSTRACT

Natural photosensitizers have emerged as promising candidates for photodynamic therapy (PDT) owing to their structural diversity, favorable biocompatibility, and broad biological activities. However, their significance extends beyond their natural origin, as they represent the products of chemo‐biodiversity shaped by millions of years of evolutionary adaptation to diverse ecological pressures. This review examines natural photosensitizers through a chemo‐biodiversity perspective, emphasizing how evolutionary diversification has generated structurally distinct photoactive scaffolds with unique photophysical and photobiological properties relevant to cancer therapy. Attention is given to the relationships between molecular architecture, excited‐state dynamics, reactive oxygen species generation, and therapeutic performance, highlighting how structural features govern photodynamic efficiency and biological responses. The review further discusses how nanotechnology‐based engineering strategies can overcome intrinsic limitations, including poor aqueous solubility, aggregation, photoinstability, and limited tumor selectivity. Recent advances in multifunctional nanoplatforms, molecular engineering, and combination therapies are critically evaluated alongside current translational challenges, including manufacturing, regulatory considerations, and clinical development. By integrating natural product chemistry, photophysics, photobiology, and nanotechnology within a unified conceptual framework, this review demonstrates that chemo‐biodiversity provides a rational foundation for the discovery of next‐generation natural photosensitizers. Harnessing nature's evolutionary molecular diversity offers new opportunities to develop safer, more effective, and clinically translatable photodynamic therapies.

Natural photosensitizers, shaped by chemo‐biodiversity and evolution, offer diverse photoactive scaffolds for PDT. This review highlights their structure–activity relationships, photophysical properties, and nanotechnology‐based strategies to enhance efficacy, while addressing translational challenges and demonstrating how nature's molecular diversity drives next‐generation, clinically translatable PDT agents.

1. Introduction

Cancer continues to rank among the foremost causes of death globally, accounting for close to 10 million fatalities each year, even with major progress in surgical techniques, chemotherapy, immunotherapy, and radiotherapy [1, 2]. Despite these advances, many conventional treatment strategies remain limited by systemic side effects, inadequate tumor selectivity, and the development of multidrug resistance [3]. In this context, light‐based therapies, particularly photodynamic therapy (PDT) and photothermal therapy (PTT), have re‐emerged as attractive alternatives due to their minimally invasive nature and high spatial precision. By enabling localized activation within tumor tissues while largely sparing adjacent healthy structures, these approaches represent a shift from broad systemic treatment to controlled, site‐specific intervention [4].

Central to both PDT and PTT is the photosensitizer [5], a molecule capable of absorbing light and converting that energy into either ROS or heat [6]. In PDT, light activation of the PS results in ROS generation, which induces oxidative damage to cellular components and tumor vasculature, ultimately leading to cancer cell death. In contrast, PTT relies on efficient light‐to‐heat conversion to produce localized hyperthermia that disrupts tumor integrity [7]. Since the clinical approval of Photofrin in the 1990s, numerous synthetic PSs, including porphyrins, chlorins, and phthalocyanines, have been investigated [8, 9]. However, issues such as limited aqueous solubility, prolonged cutaneous photosensitivity, photobleaching, and off‐target tissue accumulation have constrained their broader clinical application [9, 10].

These limitations have encouraged growing interest in natural photosensitizers derived from plants, fungi, marine organisms, and microorganisms, many of which inherently contain light‐responsive chromophores [11]. Compounds such as hypericin from Hypericum perforatum [12], curcumin from Curcuma longa [13], chlorophyll derivatives [14], and fungal perylenequinones [15]. They have demonstrated promising photochemical properties. Compared with synthetic counterparts, these natural molecules often offer improved biocompatibility, biodegradability, structural diversity, and accessibility from renewable sources [16]. Importantly, many exhibit absorption profiles that overlap with the so‐called “therapeutic window” in the red to near‐infrared (NIR) region, where tissue penetration is enhanced [17]. For instance, hypericin, with absorption peaks around 550 nm and 590–600 nm (in organic solvents), displays a high singlet oxygen quantum yield, supporting strong photooxidative activity in tumor models. Curcumin, when incorporated into suitable nanocarriers, has shown both photodynamic and photothermal potential, illustrating the multifunctionality that natural PSs can achieve through formulation strategies [18, 19].

From a chemo‐biodiversity perspective, nature's vast chemical diversity, shaped through evolutionary pressures for survival and adaptation, offers a rich platform for therapeutic discovery [20]. Unlike synthetic chemical libraries that are typically designed around predefined pharmacophores, naturally occurring metabolites emerge from dynamic interactions between organisms and their environments, including exposure to solar radiation, oxidative stress, microbial competition, predation, and environmental signaling [21]. These selective pressures have driven the evolution of structurally diverse chromophores with specialized photochemical and redox‐responsive functions. Consequently, many natural compounds possess intrinsic light‐harvesting, energy‐transfer, and photooxidative properties that are directly relevant to photodynamic and photothermal cancer therapy [20].

In biological systems, photoactive metabolites frequently serve protective or regulatory roles. Tetrapyrrolic pigments such as chlorophylls and bacteriochlorophylls participate in photosynthetic energy transfer, while flavins, quinones, carotenoids, and polyphenolic compounds contribute to oxidative defense, stress adaptation, antimicrobial activity, and photoprotection [22]. In fungi and higher plants, several photoresponsive secondary metabolites serve as ecological defense molecules that generate ROS upon light exposure to deter pathogens and herbivores [23, 24]. Marine algae and cyanobacteria similarly synthesize structurally diverse pigments that regulate photon energy absorption and dissipate excess oxidative stress in highly irradiated environments [25, 26]. Importantly, the same photochemical behaviors that support these ecological functions, including efficient intersystem crossing (ISC) ROS generation, electron transfer, and non‐radiative energy dissipation, can be therapeutically redirected to selectively destroy tumors upon controlled light activation [27].

The chemo‐biodiversity of natural photosensitizers is further reflected in their extensive structural and photophysical diversity. Natural chromophores encompass tetrapyrroles, chlorins, bacteriochlorins, anthraquinones, flavins, polyphenols, xanthones, thiophenes, and polyacetylenes, each exhibiting distinct absorption characteristics, excited‐state dynamics, ROS‐generation pathways, and photothermal conversion efficiencies [28]. Such diversity expands the available phototherapeutic toolbox beyond conventional synthetic porphyrinoid systems and provides opportunities for tailoring excitation wavelength, tissue penetration depth, oxygen dependence, and biological targeting behavior. In several cases, the photophysical properties of these molecules appear to reflect evolutionary optimization toward efficient energy transfer and excited‐state regulation under biologically relevant conditions [29].

Beyond therapeutic efficacy, the exploration of natural photosensitizers also aligns with emerging principles of sustainable, environmentally conscious photomedicine. Many naturally derived chromophores originate from renewable biological resources and may be produced using green extraction methods, microbial fermentation, metabolic engineering, or synthetic biology approaches [30]. Compared with several conventional synthetic photosensitizers that require multistep synthesis and metal‐containing components, naturally sourced compounds may offer advantages related to biodegradability, ecological compatibility, and reduced environmental burden. Nevertheless, sustainability considerations must also account for challenges such as biodiversity depletion, seasonal variability, low metabolite yield, and the ecological consequences of large‐scale harvesting. Therefore, future progress in natural photomedicine will require balanced integration of ethical bioprospecting, scalable biomanufacturing strategies, and environmentally responsible nanotechnological design [30, 31].

Collectively, natural photosensitizers should not be viewed merely as alternative therapeutic molecules, but rather as biologically evolved photochemical systems whose ecological origins, molecular diversity, and adaptive functions provide valuable templates for next‐generation precision photomedicine. Advances in biotechnology and nanotechnology are further enhancing the translational potential of natural photosensitizers. Metabolic engineering and microbial biosynthesis now offer scalable routes for producing rare chromophores, while nanoformulation strategies improve solubility, stability, tumor accumulation, and phototherapeutic efficiency [32, 33]. These developments are accelerating the integration of natural photoactive compounds into multifunctional and clinically adaptable therapeutic platforms [34, 35]. The evolution of light‐activated oncology toward image‐guided therapy, photoimmunotherapy, and deep‐tissue photomedicine further underscores the relevance of natural photosensitizers in precision cancer treatment [36, 37]. Unlike conventional reviews focused primarily on photodynamic mechanisms or isolated classes of natural photosensitizers, this review integrates chemo‐biodiversity, evolutionary photochemistry, translational nanotechnology, and sustainability considerations into a unified framework for next‐generation light‐activated cancer therapy.

2. Molecular Basis of Photoactivity in Natural Photosensitizers

Natural photosensitizers display remarkable structural and photochemical diversity, yet they share a fundamental property: the capacity to absorb photons and convert that energy into controlled oxidative or thermal responses. In nature, this capability supports roles in protection, communication, and defense. In oncology, the same principle underlies their value in light‐activated therapies, where selective activation and biocompatibility are essential. A clear understanding of the molecular features responsible for photoactivity is therefore crucial for optimizing therapeutic performance and guiding the development of next‐generation phototherapeutic agents. Across botanical, fungal, marine, and microbial sources, photoactivity is typically embedded within a chromophoric core characterized by extended π‐conjugation, planar geometry, and the presence of heteroatoms. These structural attributes influence light absorption characteristics, excited‐state lifetimes, ISC efficiency, and ultimately ROS generation capacity, parameters that directly impact photodynamic effectiveness.

2.1. Tetrapyrrolic Macrocycles

Tetrapyrrolic macrocycles, including porphyrins, chlorins, and bacteriochlorins (Figure 1), represent a prominent class of naturally occurring chromophores. These systems possess a highly conjugated aromatic framework that enables strong absorption in the visible and near‐infrared regions. Endogenous examples include heme, chlorophylls, and bacteriochlorophylls, which play essential biological roles in oxygen transport and photosynthesis. Extended analogues such as phthalocyanines and naphthalocyanines exhibit even greater red‐shifted absorption into the NIR region [38]. Owing to their favorable photophysical properties, tetrapyrrolic macrocycles remain central to PDT applications in oncology and have also demonstrated utility in antimicrobial PDT.

FIGURE 1.

Structural comparison of porphyrin, chlorin, and bacteriochlorin macrocycles.

All three consist of four pyrrole rings linked by methine bridges. The arrows indicate the progressive structural modifications among the tetrapyrrolic macrocycles, illustrating the reduction of pyrrole double bonds that distinguishes porphyrins, chlorins, and bacteriochlorins.

Collectively, tetrapyrrolic macrocycles yield one of the most translationally advanced classes of naturally inspired photosensitizers due to their strong absorption characteristics, relatively high singlet oxygen quantum yields, and established clinical history [30]. Their evolutionary optimization for light harvesting and electron transfer in photosynthetic systems provides highly efficient excited‐state behavior that remains difficult to fully replicate synthetically [39, 40]. Nevertheless, several limitations continue to constrain broader clinical utility, including prolonged photosensitivity, aggregation tendencies, oxygen dependence, and manufacturing complexity. While chlorins and bacteriochlorins offer superior, red‐shifted absorption and improved tissue penetration compared with classical porphyrins, issues related to pharmacokinetics, tumor selectivity, and large‐scale standardization remain important translational barriers. These considerations highlight the need for formulation engineering and the integration of multifunctional therapeutics rather than relying on intrinsic photophysical performance alone.

2.1.1. Porphyrins

The photodynamic performance of porphyrins is fundamentally rooted in their highly conjugated aromatic tetrapyrrolic macrocycle, whose rigid planar geometry supports extensive π‐electron delocalization and relatively stable excited‐state formation [41]. Evolutionarily derived, naturally occurring porphyrinoids such as heme and protoporphyrin derivatives have emerged as central mediators of electron transfer, oxygen transport, and redox catalysis within biological systems. These ancestral biochemical functions likely contributed to the exceptional excited‐state stability and redox versatility that now underpin their therapeutic utility in PDT. Structurally, the porphyrin macrocycle exhibits strong absorption in the Soret band due to intense π→π* transitions; however, the lower extinction coefficients of the red‐shifted Q‐bands impose important translational limitations, as therapeutic activation in vivo requires deeper tissue penetration within the red and near‐infrared optical window [42, 43].

This inherent photophysical imbalance illustrates one of the major evolutionary trade‐offs of naturally occurring porphyrinic systems. While evolution optimized porphyrins primarily for biological electron‐transfer efficiency and metabolic coordination rather than for therapeutic tissue penetration, clinical photomedicine requires precisely the opposite balance: strong long‐wavelength absorption, controlled ROS generation, and minimal systemic toxicity [41, 44]. Consequently, first‐generation porphyrins such as Photofrin frequently exhibit suboptimal tumor selectivity, prolonged cutaneous photosensitivity, and heterogeneous intracellular localization. Their planar aromatic architecture also promotes π–π stacking and aggregation under physiological conditions, thereby substantially reducing the yield of the triplet state and singlet oxygen production via self‐quenching mechanisms. From a photophysical perspective, aggregation perturbs excitonic coupling and facilitates non‐radiative decay pathways that compete with productive ISC [45, 46].

Biologically, porphyrins often accumulate within mitochondria, lysosomes, and tumor‐associated vasculature because of their amphiphilic behavior and affinity for lipoprotein transport systems. Although this contributes to broad photodynamic activity, it may also increase off‐target oxidative injury in normal tissues [47, 48]. In hypoxic tumors, their heavy dependence on Type II oxygen‐mediated photochemistry further limits therapeutic effectiveness. These limitations have driven the development of semisynthetic porphyrinoid derivatives, metal‐coordinated systems, and nanostructured formulations to improve excited‐state control, tumor specificity, and phototherapeutic precision. Nevertheless, despite the emergence of newer photosensitizer classes, porphyrins remain mechanistically foundational because their molecular architecture continues to define the structural and photophysical benchmark against which most natural and synthetic photosensitizers are evaluated.

2.1.2. Chlorins

The superior phototherapeutic behavior of chlorins relative to classical porphyrins originates from subtle but highly consequential structural modification of the tetrapyrrolic macrocycle. Notable examples are m‐tetrahydroxyphenylchlorin (Temoporfin or Foscan) [49], benzoporphyrin derivative (Verteporfin) [50], and Radachlorin (now Bremachlorin) [51]. Chlorin e6, derived from natural chlorophyll, has also been widely studied and clinically formulated, either as the trisodium salt photodithazine [52] or in polyvinylpyrrolidone‐based preparations [53]. The mono‐L‐aspartyl derivative of chlorin e6, known as Talaporfin sodium (Laserphyrin or LS11), has seen clinical use in Japan [54] has been used in Japan. Other PSs that have advanced to clinical trials include the pyropheophorbide derivative HPPH [55] and tin ethyl etiopurpurin (SnET2). Partial hydrogenation of one pyrrolic double bond disrupts macrocyclic aromatic symmetry and alters π‐electron distribution, thereby reducing the HOMO–LUMO energy gap and producing a pronounced bathochromic shift of the Q‐band absorption into the 650–700 nm region [56]. This red shift significantly improves photon penetration through biological tissue while simultaneously increasing molar absorptivity within the therapeutic optical window. Evolutionarily, chlorin‐based scaffolds derive largely from chlorophyll biosynthetic systems optimized for solar energy capture and directional electron transfer during photosynthesis. The resulting molecular architecture, therefore, reflects highly refined excited‐state control mechanisms that favor efficient energy migration and long‐lived triplet‐state formation [57, 58].

The reduced symmetry of chlorins not only enhances red‐light absorption but also facilitates more efficient ISC and singlet oxygen generation compared with many first‐generation porphyrins [59]. These electronic characteristics directly contribute to their greater photodynamic potency and help explain the successful clinical translation of chlorin‐derived agents such as temoporfin and talaporfin sodium [44]. At the same time, the extended conjugation and partially reduced macrocycle that improve photoactivity may also increase susceptibility to oxidative degradation and photobleaching during prolonged irradiation. Their predominantly hydrophobic character further promotes aggregation in aqueous environments, where intermolecular π–π interactions can perturb excited‐state dynamics and reduce the efficiency of ROS generation through excitonic self‐quenching [60, 61].

Within biological systems, chlorins frequently demonstrate enhanced intracellular uptake and preferential localization within mitochondria and endoplasmic reticulum compartments, thereby facilitating oxidative stress‐mediated apoptotic signaling following light activation [62]. However, the strong dependence of many chlorin systems on Type II singlet‐oxygen photochemistry creates a major limitation under hypoxic tumor conditions, where restricted oxygen availability substantially compromises ROS production despite otherwise favorable photophysical properties [63, 64]. These constraints have driven increasing interest in multifunctional chlorin‐based platforms capable of integrating photothermal conversion, oxygen‐generating nanostructures, or electron‐transfer‐mediated Type I photochemistry to improve therapeutic performance within complex tumor microenvironments. Although chlorins remain among the most clinically advanced naturally inspired photosensitizers, their future translational success will likely depend on overcoming oxygen dependence and improving photochemical stability under physiologically heterogeneous conditions.

2.1.3. Bacteriochlorins

Bacteriochlorins represent another important subgroup of tetrapyrrolic macrocycles, characterized by even further red‐shifted absorption into the near‐infrared region [65]. They are distinguished by the reduction of two pyrrolic double bonds within the macrocyclic structure (Figure 1). This modification profoundly perturbs electronic symmetry and substantially narrows the HOMO–LUMO energy gap, producing intense absorption bands in the near‐infrared region, approximately 700–800 nm. Such long‐wavelength absorption reflects evolutionary adaptation within photosynthetic bacteria inhabiting low‐light ecological niches, where efficient harvesting of low‐energy photons was essential for survival [66]. The resulting molecular architecture, therefore, embodies highly optimized excited‐state energy‐transfer systems capable of utilizing photon energies inaccessible to many other naturally occurring chromophores. One example is the palladium‐containing bacteriophaeophorbide derivative known as TOOKAD [67], along with its water‐soluble analogue, TOOKAD Soluble, both of which have undergone clinical investigation for prostate cancer [68]. More recently, the bacteriochlorin derivative LUZ11 [69] entered clinical trials for advanced head and neck cancer in Portugal (ClinicalTrials.gov NCT02070432). Beyond these agents, several additional bacteriochlorin‐based compounds have been explored for both oncological [70] and antimicrobial [71] applications.

Evolutionary and structural adaptations fundamentally distinguish bacteriochlorins from chlorins, rather than merely extending their absorption further into the near‐infrared region. Whereas chlorins evolved primarily within oxygenic photosynthetic systems optimized for visible‐light harvesting under aerobic conditions, bacteriochlorins evolved in anoxygenic photosynthetic bacteria inhabiting low‐light, frequently hypoxic ecological environments [72, 73]. This distinction has likely contributed to the development of highly specialized macrocyclic architectures capable of efficient low‐energy photon utilization and excited‐state stabilization under energetically constrained conditions. The additional reduction of the tetrapyrrolic framework not only intensifies NIR absorption but also alters electron‐density distribution, vibronic coupling behavior, and triplet‐state energetics in ways that substantially modify photochemical reactivity relative to chlorins [74, 75].

These electronic differences have important biological consequences. The exceptionally strong NIR absorption of bacteriochlorins enables activation at wavelengths associated with reduced tissue scattering and deeper tumor penetration, making them particularly attractive for treating highly pigmented or deeply seated malignancies inaccessible to many chlorin‐based systems [76]. At the same time, the increased conformational flexibility and partially saturated macrocycle render bacteriochlorins substantially more susceptible to photooxidation and oxidative self‐degradation, which frequently result in rapid photobleaching and reduced photochemical durability under prolonged irradiation [76]. Their high hydrophobicity further promotes aggregation in physiological environments, perturbing excitonic interactions and altering the efficiency of ROS generation. Unlike several chlorins that maintain relatively stable singlet oxygen production under controlled conditions, bacteriochlorins often exhibit more dynamic and environment‐sensitive excited‐state behavior, particularly within heterogeneous tumor microenvironments where oxygen gradients, membrane polarity, and local redox conditions strongly influence photochemical pathways [77]. Current translational strategies increasingly focus on multifunctional bacteriochlorin systems that integrate photothermal conversion, hypoxia‐adaptive radical photochemistry, and nanostructure‐mediated excited‐state stabilization to preserve their exceptional deep‐tissue activation capability while overcoming intrinsic photochemical instability.

2.2. Perylenequinones and Anthraquinones

Quinone‐derived chromophores constitute one of the most chemically and evolutionarily distinct classes of natural photosensitizers. Unlike tetrapyrrolic macrocycles, which evolved primarily for light harvesting and energy transfer, quinones function predominantly as redox‐active secondary metabolites involved in oxidative defense, allelopathy, microbial competition, and host–pathogen interactions [78, 79]. Their conjugated aromatic frameworks containing electron‐deficient carbonyl groups promote reversible redox cycling and photoinduced electron transfer, enabling the generation of superoxide (O₂•⁻), hydroxyl radicals (OH), hydrogen peroxide (H₂O₂), and singlet oxygen (¹O₂) following photoexcitation [80, 81]. The structural evolution of quinone‐based chromophores from the conserved anthraquinone nucleus to the three principal perylenequinone classes (Classes A–C) is illustrated in Figure 2, highlighting how progressive oxidative coupling, ring fusion, and functional‐group diversification have expanded their chemical complexity and photochemical versatility.

FIGURE 2.

Chemo‐biodiversity‐driven structural diversification of quinone‐based natural photosensitizers. Representative chemical structures illustrate the transition from the conserved anthraquinone core to the three major classes of naturally occurring perylenequinones: Class A (Altertoxin I), Class B (Phleichrome), and Class C (Rhodoaphin‐be).

From a chemo‐biodiversity perspective, fungal perylenequinones represent an outstanding example of evolutionary molecular diversification. Although biosynthesized from a common polyketide‐derived perylene core, modifications in ring topology, cyclization, axial chirality, and oxygenated substituents generate structurally distinct chromophores with markedly different photophysical properties [82]. In contrast to chlorophyll‐derived tetrapyrroles that evolved to maximize solar energy capture, fungal perylenequinones evolved predominantly as photoactivated virulence factors, enabling species such as Cercospora, Elsinoë, and Shiraia to generate ROS under natural illumination and induce oxidative damage in host tissues [82]. These evolutionary adaptations underpin their ability to undergo both Type I and Type II photochemical pathways, with the balance between electron‐transfer and energy‐transfer mechanisms strongly influenced by molecular structure, π‐conjugation, substituent pattern, solvent polarity, and oxygen availability. Representative natural quinone photosensitizers, their structural characteristics, photophysical behavior, and therapeutic applications are summarized in Table 1.

TABLE 1.

Representative quinone‐derived natural photosensitizers: Structural diversity, photophysical characteristics, and translational significance.

Compound	Structural Class	Natural Source	Structural Features	Photochemical Behavior	Advantages of PDT	Major Limitations
Hypocrellin A	Class B perylenequinone	Shiraia bambusicola	Hexacyclic perylenequinone with extended π‐conjugation and axial chirality	Mixed Type I/Type II; high 1O2 generation	Low dark toxicity, rapid clearance, high photostability, minimal aggregation	Poor aqueous solubility; requires formulation for systemic delivery
Cercosporin	Class A perylenequinone	Cercospora spp.	Pentacyclic perylenequinone with a methylenedioxy bridge	Efficient Type I/Type II ROS generation	One of the most potent natural ROS generators, with strong photodynamic activity	Visible‐light activation limits tissue penetration; fungal phototoxin
Elsinochromes	Class A perylenequinone	Elsinoë spp.	Pentacyclic aromatic perylenequinones	Predominantly Type II	High singlet oxygen generation	Limited biological and translational studies
Shiraiachromes	Class B perylenequinone	Shiraia spp.	Highly oxygenated hexacyclic perylenequinones	Mixed Type I/Type II	Good photodynamic efficacy; structurally related to hypocrellins	Poor aqueous solubility; limited pharmacokinetic data
Emodin	Anthraquinone	Rheum, Polygonum, Aloe spp.	Hydroxylated anthraquinone	Predominantly Type I electron transfer	Potential activity under hypoxic conditions; multifunctional anticancer effects	Lower ROS yield and weaker visible‐light absorption than perylenequinones
Aloe‐emodin	Anthraquinone	Aloe vera and related species	Hydroxylated anthraquinone	Type I ROS generation	Induces apoptosis following photoactivation; low‐cost natural source	Rapid metabolism and limited photostability
Aminoanthraquinone derivatives	Anthraquinone	Semi‐natural derivatives of natural anthraquinones	Amino‐substituted anthraquinone core	Electron‐transfer mediated Type I photochemistry	Efficient superoxide and H2O2 generation; promising for hypoxia‐adaptive PDT	Increased risk of redox cycling and dark toxicity

Representative natural quinone‐derived photosensitizers illustrating how structural diversification from the conserved anthraquinone scaffold to more complex perylenequinone architectures influences π‐conjugation, excited‐state dynamics, ROS generation pathways, and translational suitability for PDT.

Among naturally occurring perylenequinones, hypocrellin A has emerged as one of the most promising PDT scaffolds because of its high singlet oxygen quantum yield, low dark toxicity, rapid biological clearance, and favorable photostability, whereas cercosporin remains one of the most efficient naturally occurring ROS generators despite its limited tissue penetration resulting from visible‐light activation [5, 82]. Other fungal metabolites, including elsinochromes and shiraiachromes, further demonstrate the remarkable photochemical diversity generated through fungal secondary metabolism. Conversely, anthraquinones such as emodin, aloe‐emodin, and aminoanthraquinone derivatives generally exhibit lower photosensitizing efficiencies but possess pronounced electron‐transfer capabilities that favor radical‐mediated Type I photochemistry, making them attractive candidates for hypoxia‐adaptive PDT [83, 84]. These observations demonstrate that quinone‐derived photosensitizers represent an alternative evolutionary strategy to tetrapyrroles, where structural diversification primarily optimizes redox chemistry rather than photon harvesting. Nevertheless, their clinical translation remains constrained by redox‐associated dark toxicity, aggregation, and variable pharmacokinetics, emphasizing the need for structure‐guided molecular engineering and nanotechnology‐assisted delivery systems to maximize therapeutic selectivity and photodynamic performance.

The progressive increase in molecular complexity from simple anthraquinones to perylenequinones is reflected not only in structural diversity but also in their photodynamic behavior. Extension of the conjugated π‐system shifts light absorption toward longer wavelengths and generally enhances the efficiency of ISC and singlet oxygen production. Although representative compounds such as hypocrellin A and cercosporin display excellent photodynamic performance, their reported absorption maxima, excitation wavelengths, and singlet oxygen quantum yields vary with molecular structure and experimental conditions. These observations further illustrate how subtle structural modifications govern the photophysical and biological properties of naturally occurring quinone photosensitizers.

2.3. Polyphenolic Chromophores

Polyphenolic chromophores represent one of the largest and most chemically sophisticated families of plant secondary metabolites, arising from millions of years of evolutionary adaptation to fluctuating environmental conditions. Unlike tetrapyrrolic macrocycles that evolved to harvest solar energy or quinones that function predominantly as redox‐active defense metabolites, polyphenols emerged primarily to regulate oxidative homeostasis while simultaneously protecting plants against ultraviolet irradiation, pathogen invasion, herbivory, and abiotic stress [85]. This remarkable ecological versatility has generated an enormous repertoire of structurally diverse phenolic scaffolds, including flavonoids, curcuminoids, stilbenes, xanthones, and naphthodianthrones, whose common feature is an electronically conjugated aromatic framework that can fine‐tune electron transfer and radical stabilization [86]. Representative structural scaffolds illustrating this chemical diversity are shown in Figure 3. Rather than passive antioxidant molecules, polyphenols are dynamic redox systems whose chemical architecture has been evolutionarily refined to modulate oxidative processes in response to cellular and environmental demands.

FIGURE 3.

Structural diversity of representative polyphenolic chromophores used as natural photosensitizers. The progressive variation in aromatic conjugation, hydroxylation, and molecular rigidity underpins differences in photophysical behavior, reactive oxygen species generation, and photodynamic therapeutic potential.

This evolutionary optimization is evident in the intimate relationship between molecular structure and photochemical behavior. The photophysical properties of polyphenols are dictated by the extent of π‐electron conjugation, hydroxylation pattern, carbonyl substitution, and the ability to undergo excited‐state intramolecular proton transfer (ESIPT) or keto–enol tautomerism [87, 88]. These structural characteristics influence frontier molecular orbital energies, excited‐state lifetimes, ISC efficiency, and ultimately the balance between antioxidant activity and photoinduced ROS generation. In their ground state, phenolic hydroxyl groups readily donate hydrogen atoms or electrons to neutralize reactive species, thereby protecting biological systems from oxidative injury. Upon photoexcitation, however, redistribution of electron density can redirect these same molecules toward pro‐oxidant pathways, facilitating the formation of singlet oxygen, superoxide radicals, or hydroxyl radicals depending on molecular structure, oxygen availability, and the surrounding microenvironment [89, 90]. Relatively small modifications, including additional hydroxyl groups, methoxy substitution, extension of π‐conjugation, or increased molecular planarity, can profoundly alter photodynamic efficiency by affecting charge‐transfer dynamics, triplet‐state formation, and ROS quantum yield.

Among naturally occurring polyphenolic photosensitizers, curcumin and hypericin illustrate two distinct evolutionary solutions to photoactive chemistry. Curcumin, isolated from Curcuma longa, possesses a conjugated diarylheptanoid framework in which the β‐diketone bridge undergoes keto–enol tautomerism, extending electron delocalization and enabling visible‐light absorption [91]. Although this architecture contributes to broad biological activities, including antioxidants, anti‐inflammatory, and anticancer effects, it also renders curcumin susceptible to rapid metabolic degradation, poor aqueous solubility, and limited excitation beyond the blue‐visible region of the spectrum. Consequently, much of its recent development has focused on nanoformulation and molecular engineering to improve photostability, tumor accumulation, and ROS generation [92]. Hypericin, in contrast, represents a far more extensively conjugated naphthodianthrone pigment isolated from Hypericum perforatum. Its rigid polycyclic aromatic structure promotes exceptionally efficient ISC and one of the highest singlet oxygen quantum yields reported among natural photosensitizers, while extensive π‐delocalization favors mitochondrial localization and potent apoptotic responses following irradiation [93]. These characteristics have positioned hypericin as one of the most promising naturally derived PDT agents despite persistent challenges associated with hydrophobicity and formulation.

Other members of the polyphenol family further demonstrate how evolutionary diversification has produced distinct photochemical behaviors from a common phenolic framework. Flavonoids such as quercetin possess multiple hydroxyl substituents that confer strong antioxidant capacity but generally limit triplet‐state formation because rapid excited‐state deactivation competes with ISC [94]. Nevertheless, photoexcitation can shift quercetin toward pro‐oxidant activity through electron‐transfer reactions that can induce mitochondrial dysfunction, DNA damage, and apoptosis in tumor cells. Similarly, stilbenes such as resveratrol display comparatively weak intrinsic photosensitizing ability but remain attractive multifunctional scaffolds because photoactivation can complement their established anti‐inflammatory, immunomodulatory, and chemopreventive activities [95, 96]. These examples illustrate that the therapeutic value of polyphenolic chromophores extends beyond ROS production alone, encompassing synergistic modulation of multiple cellular pathways involved in cancer progression.

The antioxidant–pro‐oxidant behavior of polyphenols represents one of the most intriguing consequences of their evolutionary chemistry. Rather than representing contradictory biological functions, these seemingly opposing activities arise from the same electronically adaptable molecular framework, whose response depends on the excitation state, oxygen concentration, intracellular localization, and the surrounding redox environment [97, 98]. This redox plasticity distinguishes polyphenolic photosensitizers from both tetrapyrrolic macrocycles, which primarily rely on energy transfer, and quinone‐derived chromophores, whose activity is dominated by electron‐transfer chemistry. However, their relatively weak long‐wavelength absorption, limited triplet‐state yields, susceptibility to metabolic degradation, and variable bioavailability continue to constrain clinical translation [99]. Future development should therefore emphasize rational structural optimization and nanotechnology‐assisted delivery systems that preserve the inherent biological versatility of polyphenols while enhancing photophysical performance, tumor selectivity, and therapeutic precision.

2.4. Flavins

Flavins represent a unique class of naturally occurring chromophores whose photodynamic properties originate from their dual roles as redox cofactors and photoresponsive biological molecules. Derived from riboflavin (vitamin B₂), flavins comprise a family of isoalloxazine‐containing compounds, including flavin mononucleotide (FMN) and flavin adenine dinucleotide [100], which are universally distributed across bacteria, fungi, plants, and animals. Unlike tetrapyrroles, which evolved for light harvesting, or quinones and polyphenols, which primarily regulate oxidative chemistry, flavins evolved to facilitate enzymatic oxidation–reduction reactions essential for cellular metabolism. Their widespread conservation reflects the remarkable versatility of the isoalloxazine ring system, whose reversible redox chemistry enables participation in one‐electron and two‐electron transfer reactions while simultaneously conferring intrinsic photoactivity under blue‐light irradiation. Flavins occupy a unique position at the interface of metabolism and photochemistry, providing a natural molecular framework that has been increasingly exploited for antimicrobial and anticancer PDT [101].

The photophysical behavior of flavins is governed by the isoalloxazine chromophore, a rigid tricyclic heteroaromatic system with an extended π‐conjugated network and multiple nitrogen atoms that can stabilize multiple oxidation states [102]. Following absorption of blue light (approximately 370–450 nm), flavins undergo efficient excitation to singlet states, followed by ISC to long‐lived triplet states that readily participate in both Type I and Type II photochemical pathways [103]. The excited triplet state may transfer energy directly to molecular oxygen to generate singlet oxygen or undergo electron‐transfer reactions producing superoxide radicals, hydrogen peroxide, and hydroxyl radicals. Unlike many naturally occurring photosensitizers, however, flavins exhibit exceptionally rich excited‐state chemistry because their photoreactivity is strongly influenced by proton‐coupled electron transfer, solvent polarity, oxygen concentration, and interactions with surrounding proteins. Protein binding can profoundly alter absorption spectra, excited‐state lifetimes, and ROS quantum yields, allowing evolution to fine‐tune flavin photochemistry for specific biological functions rather than maximizing ROS production alone [104, 105].

This intimate relationship between molecular structure and biological function distinguishes flavins from virtually every other class of natural photosensitizer. The isoalloxazine nucleus remains highly conserved throughout evolution, whereas functional diversity is generated primarily through modifications of the ribityl side chain and interactions with different flavoproteins rather than extensive alterations of the chromophore itself (Figure 4). Flavin biodiversity is expressed predominantly through functional diversification rather than structural diversification, illustrating an alternative evolutionary strategy in which a conserved photoactive scaffold acquires distinct catalytic and photochemical properties depending on its protein environment [106].

FIGURE 4.

Structural diversification of naturally occurring flavins. Riboflavin (vitamin B₂) represents the parent isoalloxazine chromophore from which flavin mononucleotide (FMN) and flavin adenine dinucleotide are biosynthetically derived through sequential phosphorylation and adenylation.

Among naturally occurring flavins, riboflavin remains the most extensively investigated photosensitizer because of its excellent biocompatibility, low systemic toxicity, and ability to generate both singlet oxygen and radical species upon visible‐light irradiation. Riboflavin‐mediated photochemistry has established clinical applications in corneal collagen cross‐linking for keratoconus and demonstrates considerable promise for antimicrobial PDT through oxidative damage to bacterial membranes, proteins, and nucleic acids [107]. Its naturally occurring phosphorylated derivatives, FMN and FAD, exhibit comparable photochemical behavior but possess altered redox potentials and intracellular localization owing to their additional phosphate and adenine moieties. These derivatives also illustrate how relatively modest structural modifications can significantly influence cofactor binding, electron‐transfer kinetics, and photodynamic efficiency within biological systems [107].

Although flavins possess several characteristics desirable for photodynamic applications, including excellent biosafety, endogenous biocompatibility, and efficient ROS generation, their clinical utility remains constrained by relatively weak absorption in the therapeutic window (650–900 nm) [108], rapid photobleaching, and oxygen‐dependent photochemistry. Recent advances in molecular engineering, supramolecular assembly, and nanotechnology have therefore focused on extending visible‐light absorption, enhancing photostability, and improving tumor selectivity without compromising the intrinsic biocompatibility of flavin‐based chromophores. These developments highlight how a metabolically conserved cofactor can be transformed into a versatile platform for next‐generation natural photosensitizers while preserving the evolutionary principles that originally defined its biological function [109].

2.5. Polyacetylenes And Thiophenes

Polyacetylenes and thiophenes constitute a distinctive group of naturally occurring photoactive metabolites whose biological functions are closely associated with chemical defense rather than primary metabolism [110]. Predominantly produced by members of the Asteraceae, Apiaceae, and Araliaceae, these compounds have evolved as protective secondary metabolites that enhance plant survival against herbivores, nematodes, fungi, bacteria, and insects. Their photoactivity is therefore an ecological adaptation that converts solar irradiation into localized oxidative stress, enabling plants to generate cytotoxic ROS only under illuminated conditions [111]. This strategy minimizes constitutive toxicity while maximizing defensive efficacy, illustrating an elegant evolutionary solution in which molecular structure and environmental light cooperate to regulate biological activity.

Unlike the highly conjugated aromatic systems found in tetrapyrroles or quinones, the photochemical properties of polyacetylenes arise primarily from extended carbon–carbon triple bond conjugation, whereas thiophenes (Figure 4) derive their photoactivity from sulfur‐containing heteroaromatic chromophores [112]. These structural frameworks possess markedly different electronic characteristics despite sharing the ability to undergo efficient photoexcitation under ultraviolet and visible irradiation. Conjugated acetylenic bonds lower the HOMO–LUMO energy gap, facilitating electronic excitation and charge transfer, while incorporation of sulfur within thiophene rings enhances spin–orbit coupling, promoting ISC and efficient triplet‐state formation [113]. Consequently, naturally occurring thiophenes generally exhibit higher singlet oxygen quantum yields than many polyacetylenes because the sulfur heteroatom increases the probability of triplet‐state population, thereby favoring Type II photochemical pathways. Electron‐donating substituents, molecular planarity, and the degree of conjugation further modulate absorption spectra, excited‐state lifetime, and ROS generation, demonstrating how relatively subtle structural modifications profoundly influence photodynamic performance.

Among naturally occurring thiophenes, α‐terthienyl, isolated principally from Tagetes species, remains the best‐characterized natural photosensitizer within this class. Its linear arrangement of three conjugated thiophene rings (Figure 5) provides extensive π‐electron delocalization, enabling efficient absorption of near‐ultraviolet light and exceptionally high singlet‐oxygen production upon photoactivation [114, 115]. Photoexcited α‐terthienyl readily oxidizes cellular lipids, proteins, and nucleic acids, accounting for its potent insecticidal, nematocidal, antimicrobial, and antiparasitic activities [116]. In contrast, naturally occurring polyacetylenes generally exhibit broader structural diversity, including linear, cyclic, and aromatic acetylenic frameworks that differ considerably in chain length, degree of unsaturation, and oxygenation. Representative compounds such as falcarinol and falcarindiol, abundant in carrots (Daucus carota), ginseng (Panax spp.), and other Apiaceae species, display comparatively moderate intrinsic photosensitizing activity but possess important anticancer, anti‐inflammatory, and antimicrobial properties that may synergize with photoinduced oxidative stress [117]. These observations suggest that polyacetylene‐based photosensitizers often derive their therapeutic value from integrating intrinsic pharmacological activity with photodynamic ROS generation, rather than from exceptionally high photochemical efficiency alone.

FIGURE 5.

Representative polyacetylene and thiophene photosensitizers. Falcarinol and falcarindiol illustrate the conjugated acetylenic scaffold, whereas α‐terthienyl represents the sulfur‐containing thiophene scaffold. Their distinct molecular architectures give rise to different photochemical and biological properties relevant to photodynamic therapy (PDT).

The contrasting structural evolution of polyacetylenes and thiophenes illustrates two complementary strategies through which plants have optimized photoactivated defense [112]. Sulfur incorporation into conjugated thiophene systems enhances triplet‐state formation and single‐oxygen production, whereas acetylenic carbon frameworks favor structural flexibility and chemical diversity, thereby supporting multiple biological activities beyond phototoxicity [112]. However, reliance on ultraviolet or short‐wavelength visible light limits tissue penetration, thereby constraining clinical translation. Furthermore, relatively poor aqueous solubility, photoinstability, and limited pharmacokinetic data have slowed their development as therapeutic photosensitisers. Future research should therefore focus on rational structural modification, red‐shifting of absorption wavelengths, and nanotechnology‐assisted delivery systems that preserve their unique photoactive chemistry while improving tumor selectivity, photostability, and clinical applicability.

3. Photophysical and Photobiological Mechanisms of Natural Photosensitizers

3.1. Molecular Architecture Governs Excited‐State Dynamics

PDT is fundamentally governed by the interaction between light and the electronic structure of a PS. Although all PSs follow the same general sequence of photoexcitation, the efficiency with which absorbed photon energy is converted into cytotoxic reactive oxygen species depends largely on their molecular architecture rather than on light absorption alone [118]. The remarkable chemo‐biodiversity of natural photosensitizers translates into diverse excited‐state behaviors, allowing different molecular scaffolds to exploit distinct photochemical pathways despite sharing a common photodynamic mechanism [119, 120]. Understanding these structure–photophysics relationships is therefore essential for explaining the variable therapeutic performance of natural PSs and for guiding the rational design of next‐generation phototherapeutic agents.

Upon irradiation with light corresponding to their absorption spectrum, natural PSs are promoted from the ground singlet state (S₀) to an excited singlet state (S₁ or higher), where they undergo rapid vibrational relaxation and internal conversion before returning to the lowest excited singlet staten [121]. From this state, several competing pathways become possible, including fluorescence emission, nonradiative decay, or ISC to the longer‐lived triplet state (T₁). Among these processes, triplet‐state formation is the most critical for PDT because it provides sufficient lifetime for interaction with molecular oxygen or surrounding biomolecules, ultimately leading to ROS production [122, 123]. However, the probability of ISC and the lifetime of the resulting triplet state are not universal properties; rather, they are dictated by molecular features such as π‐conjugation, molecular rigidity, heteroatom incorporation, redox‐active functional groups, and the surrounding microenvironment (Figure 6).

FIGURE 6.

Schematic representation of the dynamic energy‐level framework for natural photosensitizers [5]. Following photoexcitation, the excited singlet state (S₁) may undergo fluorescence, internal conversion, electron transfer, or intersystem crossing (ISC) to the triplet state (T₁). Charge recombination‐induced intersystem crossing (CR‐ISC) and spin–orbit charge‐transfer intersystem crossing (SOCT‐ISC) are alternative mechanisms that enhance triplet‐state formation via charge transfer. The triplet state subsequently participates in Type I and Type II photodynamic pathways, generating cytotoxic reactive oxygen species. Spin polarization states indicate the spin multiplicity of the electronic states involved in these transitions.

Natural photosensitizers illustrate how subtle structural variations can profoundly alter excited‐state dynamics. Highly conjugated tetrapyrrolic macrocycles exhibit efficient visible and near‐infrared absorption, along with long‐lived triplet states that favor energy transfer to molecular oxygen, thereby making them highly effective Type II photosensitizers [124]. In contrast, quinone‐derived chromophores possess electron‐deficient carbonyl groups that facilitate photoinduced electron transfer, thereby increasing their propensity for Type I photochemistry, particularly under oxygen‐limited conditions [125]. Polyphenolic chromophores occupy an intermediate position, where excited‐state proton transfer, hydrogen bonding, and redox‐active hydroxyl groups produce context‐dependent photochemical behavior that may exhibit antioxidant or pro‐oxidant activity depending on the irradiation conditions [126]. Flavins provide another distinct strategy, as their conserved isoalloxazine chromophore supports both one‐electron and two‐electron photochemical processes while remaining highly responsive to solvent polarity and protein binding [102]. Sulfur‐containing thiophenes represent yet another evolutionary solution, in which sulfur atoms enhance spin–orbit coupling and facilitate ISC, thereby increasing triplet‐state formation despite their comparatively small molecular frameworks [127].

Importantly, excited‐state behavior is determined not only by intrinsic molecular structure but also by supramolecular organization in biological environments. Many natural PSs exhibit concentration‐dependent aggregation, which often shortens excited‐state lifetimes through excitonic interactions and self‐quenching, reducing fluorescence and singlet oxygen generation. Interactions with proteins, lipid membranes, or nanocarrier systems can stabilize excited states, suppress aggregation, and improve ROS production. Thus, the photophysical behavior of natural photosensitizers emerges from the interplay between molecular architecture and biological microenvironment rather than from chemical structure alone. This perspective moves beyond describing individual chromophores to explain why structurally diverse natural products display markedly different photodynamic efficiencies despite sharing common photochemical principles.

3.2. Structural Determinants of Reactive Oxygen Species Generation

The therapeutic efficacy of PDT is determined by the ability of an excited photosensitizer to generate ROS. Although ROS production is traditionally classified into Type I (electron transfer) and Type II (energy transfer) pathways, these mechanisms are not mutually exclusive but represent competing photochemical processes. Their relative contributions depend on the molecular architecture of the photosensitizer, as well as environmental factors such as oxygen availability, aggregation, and the surrounding biological milieu [128]. Consequently, the structural diversity of natural photosensitizers results in distinct ROS profiles that ultimately influence therapeutic performance.

The balance between Type I and Type II photochemistry is largely dictated by excited‐state properties, particularly triplet‐state lifetime, redox potential, and electronic configuration. Photosensitizers with long‐lived triplet states generally favor energy transfer to molecular oxygen, producing singlet oxygen (¹O₂), whereas redox‐active chromophores preferentially undergo electron‐transfer reactions to generate radical species such as superoxide and hydroxyl radicals [118]. This distinction explains why tetrapyrrolic macrocycles predominantly operate via Type II pathways, whereas quinone‐derived photosensitizers often exhibit stronger Type I contributions, particularly under oxygen‐deficient conditions. Polyphenols and flavins often exhibit mixed mechanisms because their excited‐state chemistry is strongly influenced by their local microenvironment, whereas sulfur‐containing thiophenes benefit from enhanced ISC arising from sulfur‐mediated spin–orbit coupling. Importantly, aggregation, solvent polarity, protein binding, and nanocarrier encapsulation can substantially modify these photochemical pathways, demonstrating that ROS generation reflects the interplay between molecular structure and biological context rather than an intrinsic property of the chromophore.

3.3. Microenvironmental Determinants of Photodynamic Efficiency

While the intrinsic photophysical properties of a photosensitizer largely determine its capacity to generate ROS, the therapeutic outcome of PDT is equally influenced by the tumor microenvironment. Factors such as oxygen availability, pH, biomolecular interactions, and photosensitizer aggregation profoundly affect excited‐state dynamics and ROS production, often leading to substantial differences between in vitro photophysical measurements and in vivo therapeutic performance (Table 2). Consequently, evaluating natural photosensitizers solely based on their molecular structure provides an incomplete assessment of their clinical potential [129, 130].

TABLE 2.

Influence of the tumor microenvironment on natural photosensitizers.

Microenvironmental factor	Effect on PDT	Representative mitigation strategy
Tumor hypoxia	Limits singlet oxygen generation and reduces Type II PDT efficiency	Type I‐favoring photosensitizers, oxygen‐generating nanoplatforms, and catalase‐loaded nanoparticles
Photosensitizer aggregation	Causes self‐quenching, reducing triplet‐state lifetime and ROS production	Nanoencapsulation, protein binding, supramolecular formulations
Acidic tumor pH	Alters photosensitizer ionization, uptake, and redox behavior	pH‐responsive delivery systems and activatable nanocarriers
Protein and lipid interactions	Influence intracellular localization, excited‐state dynamics, and ROS generation	Targeted delivery systems and biomimetic nanocarriers

Among these factors, tumor hypoxia remains one of the principal limitations of PDT because molecular oxygen is the substrate for singlet oxygen generation via the Type II pathway. As oxygen tension decreases during tumor progression or because of vascular damage induced by PDT itself, the efficiency of energy‐transfer reactions declines markedly [131]. This limitation has renewed interest in natural photosensitizers capable of promoting electron‐transfer reactions that can retain photodynamic activity via Type I mechanisms even under reduced‐oxygen conditions. In parallel, nanotechnology‐based strategies, including oxygen‐carrying nanoparticles, catalase‐containing systems, and tumor microenvironment‐responsive formulations, have been developed to alleviate hypoxia and improve ROS production. These approaches highlight that successful PDT depends not only on the intrinsic photochemistry of the photosensitizer but also on engineering the surrounding biological environment to maximize photodynamic efficiency.

3.4. From Mechanistic Understanding to Rational Photosensitizer Design

Advances in photophysical and photobiological research have demonstrated that the therapeutic performance of natural photosensitizers is governed by an intricate interplay between molecular architecture, excited‐state dynamics, reactive oxygen species generation, and the tumor microenvironment. The development of next‐generation photosensitizers is increasingly shifting from empirical compound discovery toward mechanism‐driven molecular design [132, 133]. Rather than simply identifying new photoactive natural products, current research aims to understand how specific structural features, including conjugation length, molecular rigidity, heteroatom incorporation, and redox‐active functional groups, modulate photophysical behavior and ultimately determine therapeutic efficacy. This mechanistic perspective provides a rational framework for selecting and optimizing natural chromophores with desirable PDT characteristics.

The remarkable chemo‐biodiversity of natural products offers a diverse molecular platform for such rational design. Evolution has generated chemically distinct chromophores that collectively span a broad spectrum of photophysical properties, enabling researchers to exploit complementary mechanisms rather than relying on a single photosensitizer scaffold. These natural templates can be further optimized through structural modification, molecular hybridization, supramolecular assembly, and nanotechnology‐based delivery systems to improve light absorption, ROS generation, photostability, tumor selectivity, and pharmacokinetic performance while minimizing off‐target toxicity [134]. Future progress in natural‐product‐based PDT will therefore depend not only on discovering new photosensitizers but also on integrating natural product chemistry, photophysics, materials science, and molecular engineering to transform chemo‐biodiversity into clinically translatable phototherapeutic platforms.

4. Natural Photosensitizers Engineering for Clinical Translation

The mechanistic principles discussed in the previous section provide the foundation for natural engineering photosensitizers with improved therapeutic performance. Despite their remarkable structural diversity and favorable photophysical properties, most natural photosensitizers remain constrained by physicochemical and pharmacokinetic limitations that hinder clinical translation [135, 136]. Many of these compounds are highly hydrophobic, which reduces their bioavailability and compromises consistent light activation in biological environments [136]. To address these challenges, advances in formulation science have introduced a wide range of nano‐engineered and biomimetic delivery systems designed to improve solubility, enhance stability, and increase tumor selectivity.

Although passive tumor targeting via the enhanced permeability and retention (EPR) effect has been widely exploited in nanomedicine, growing clinical evidence indicates that the EPR effect is highly heterogeneous across tumor types and patients, thereby limiting the consistent accumulation of nanocarriers in human tumors [137, 138]. Consequently, reliance on passive targeting alone is often insufficient for effective clinical translation. Current strategies increasingly combine nanocarrier engineering with active targeting ligands, stimulus‐responsive delivery systems, and microenvironment‐responsive platforms to improve the selective delivery of natural photosensitizers.

Lipid‐ and polymer‐based nanocarriers improve PDT through complementary mechanisms rather than simply serving as drug carriers. Lipid systems primarily enhance aqueous dispersibility and protect hydrophobic chromophores from premature degradation, whereas polymeric platforms provide greater structural flexibility for controlled drug release, prolonged circulation, and surface functionalization [139, 140]. Both approaches reduce aggregation‐induced quenching, preserve excited‐state dynamics, and increase intratumoral accumulation, thereby enhancing ROS generation and therapeutic efficacy. The selection of an appropriate nanocarrier, therefore, depends not only on the physicochemical properties of the photosensitizer but also on the desired pharmacokinetic and therapeutic profile [141].

Inorganic and biomimetic nanoplatforms extend the capabilities of conventional delivery systems by introducing additional therapeutic functions. Metallic and silica‐based nanomaterials can enhance photothermal conversion, improve optical properties, or facilitate imaging, making them attractive for multimodal cancer therapy [142]. In contrast, biomimetic carriers prioritize biological compatibility by exploiting naturally derived membranes or proteins to evade immune recognition, improve cellular uptake, and prolong systemic circulation. The choice between these strategies, therefore, reflects a balance between multifunctionality, biocompatibility, manufacturing complexity, and clinical feasibility [143].

5. Translational Prospects and Future Directions

Although substantial progress has been achieved at the experimental level, bringing natural photosensitizers into routine clinical practice remains challenging. Key obstacles include compositional variability, inconsistent pharmacokinetic behavior, and difficulties in large‐scale production [31]. In contrast to synthetic porphyrins and phthalocyanines, which are produced under tightly controlled chemical conditions, natural PSs can display fluctuations in purity and photophysical performance depending on their biological source, extraction protocol, and surrounding molecular environment. While this diversity is scientifically valuable for identifying new chromophores, it complicates reproducibility and regulatory standardization [144]. Future efforts must prioritize molecular standardization and scalable manufacturing approaches. Beyond scientific optimization, successful commercialization will require compliance with Good Manufacturing Practice (GMP), standardized quality‐control procedures, and reproducible manufacturing workflows that ensure consistent purity, stability, and photophysical performance across production batches. Establishing clear regulatory pathways and quality standards will be essential to translate natural photosensitizers from laboratory‐scale production to routine clinical use [145].

Strategies such as metabolic engineering and microbial expression platforms offer promising routes for producing compounds such as hypericin, hypocrellin, and chlorophyll derivatives in controlled bioreactor systems, thereby ensuring consistent quality and supply [146, 147]. Successful translation also depends on improving pharmacokinetics and tumor specificity. Emerging smart nanocarriers that respond to tumor‐associated stimuli, such as acidic pH, hypoxic conditions, or specific enzymatic activity, provide controlled drug release and enhanced tumor accumulation while reducing off‐target toxicity [148]. Biomimetic systems, including albumin‐bound formulations and exosome‐inspired vesicles, further improve biocompatibility and circulation time, reflecting a broader shift from passive accumulation toward more refined, biologically guided targeting strategies [149, 150].

Combination treatment strategies are increasingly recognized as an effective approach to overcoming the biological limitations of PDT. Integrating natural photosensitizers with PTT, chemotherapy, immunotherapy, or hypoxia‐modulating systems enables complementary mechanisms of action that improve tumor eradication while reducing the likelihood of therapeutic resistance [151]. Rather than functioning as isolated treatment modalities, multifunctional nanoplatforms can simultaneously enhance photosensitizer delivery, modulate the tumor microenvironment, and promote synergistic therapeutic responses. These integrated strategies illustrate how advances in nanotechnology and mechanistic understanding are transforming natural photosensitizers into versatile platforms for precision cancer therapy.

Alongside technological innovation, sustainable production remains equally important for the long‐term development of natural photosensitizers. Ethical bioprospecting, green extraction methods, microbial biosynthesis, and environmentally benign nanomaterial fabrication can improve manufacturing consistency while minimizing ecological impact [152].

Although clinically approved synthetic and semisynthetic photosensitizers remain the cornerstone of PDT owing to their standardized manufacturing, well‐characterized pharmacokinetics, and regulatory maturity, natural photosensitizers offer several complementary advantages derived from their chemo‐biodiversity and structural diversity. Representative natural compounds such as hypericin, hypocrellin A, cercosporin, and chlorophyll derivatives exhibit promising photophysical and biological properties, including efficient ROS generation, favorable biocompatibility, and multifunctional therapeutic potential. However, their broader clinical translation remains limited by challenges in formulation, pharmacokinetics, standardization, and regulatory approval. A comparison of representative natural photosensitizers with clinically used synthetic or semisynthetic photosensitizers is presented in Table 3 to highlight their respective advantages, limitations, and translational readiness.

TABLE 3.

Clinical development, regulatory status, and comparative perspective of representative natural photosensitizers for PDT.

Photosensitizer	Natural Source	Representative clinically used synthetic	Comparative perspective	Clinical Trial IDs	Regulatory status	Reference
Hypericin	Hypericum perforatum (St. John's Wort)	Photofrin	Hypericin exhibits stronger visible‐light absorption, lower dark toxicity, and fluorescence‐guided imaging capability, whereas Photofrin has established regulatory approval and broader clinical validation but is associated with prolonged skin photosensitivity.	NCT00049478 (Glioma) NCT02448381 (FLASH Trial) NCT05872854 (FLASH2)	Not approved yet. Holds Fast Track status for Cutaneous T‐Cell Lymphoma but remains experimental.	[153, 154]
Curcumin	Curcuma longa (Turmeric rhizomes)	Talaporfin sodium	Curcumin offers excellent biocompatibility and multifunctional biological activity but suffers from poor bioavailability and weak tissue penetration. Talaporfin sodium provides optimized photophysical performance and established clinical efficacy.	NCT04384185 (Oral infections) NCT02724436 (Periodontitis) NCT05041075 (Cervical Neoplasia)	No (as a PDT drug). Standard curcumin is classified as GRAS for dietary use, but not for oncology.	[155]
Riboflavin (Vitamin B2)	Milk, eggs, leafy greens, or microbial fermentation.	—	—	NCT01428310 NCT01633502 (Corneal Cross‐Linking)	FDA approved as Photrexa for corneal cross‐linking. No approval for oncology.	[30, 156]
Chlorophyll derivatives (Chlorins)	Plants (e.g., spinach) and algae (precursors isolated naturally).	Padeliporfin	Natural chlorophyll derivatives provide sustainable, evolutionarily optimized tetrapyrrolic scaffolds, whereas Padeliporfin benefits from pharmaceutical optimization, standardized manufacturing, and regulatory approval	NCT04071366 (BCC) NCT03025217 (Glioma) NCT02244190 (Head/Neck Cancer)	Not approved. The specific synthetic derivative HPPH (Photochlor) has investigational status.	[157, 158]
Hypocrellins (Hypocrellin A & B)	Hypocrella bambusae (Parasitic fungus)	Verteporfin	Hypocrellin A demonstrates high ROS generation and promising PDT efficacy, but lacks the clinical evidence and regulatory maturity currently available for Verteporfin	NCT00411138 (Psoriasis / Macular degeneration using polymer variant SL052)	Not approved yet. Remains entirely experimental.	[159, 160]
Cercosporin	Cercospora species (Plant‐pathogenic fungi)	—	—	None active in mainstream human clinical trial registries (Strictly preclinical).	Not approved yet.	[161, 162]
α‐Terthienyl	Tagetes species (Marigold flowers)	—	—	None active in mainstream human clinical trial registries.	Not approved yet.	[163, 164]

Clinical trial identifiers correspond to studies registered at ClinicalTrials.gov (NCT). FDA, U.S. Food and Drug Administration; GRAS, Generally Recognized As Safe; BCC, basal cell carcinoma; FLASH, Fluorescence‐Assisted Surgical Resection and Hypericin; PDT, PDT.

6. Conclusion

Natural photosensitizers represent a unique convergence of chemo‐biodiversity, photophysics, and molecular medicine. Rather than being defined solely by their natural origin, their therapeutic value lies in the remarkable diversity of molecular architectures that have evolved to harvest light and mediate photoinduced redox processes. Understanding how these structural features govern excited‐state dynamics, reactive oxygen species generation, and biological responses provides a rational foundation for the development of more effective photodynamic therapeutics.

Despite these advances, the successful translation of natural photosensitizers into clinical practice requires overcoming several important challenges, including limited aqueous solubility, variable bioavailability, photostability, tumor hypoxia, and the inherent complexity of natural product standardization. Continued progress in nanotechnology, molecular engineering, and clinically relevant validation strategies will be essential to address these limitations and fully realize the therapeutic potential of chemo‐biodiversity.

Future advances will depend on integrating natural product chemistry, molecular engineering, nanotechnology, sustainable manufacturing, and rigorous clinical evaluation into a unified translational framework. By combining the evolutionary diversity of natural chromophores with modern engineering strategies, chemo‐biodiversity can serve not only as a source of novel photosensitizers but also as a guiding principle for the rational design of next‐generation photodynamic therapeutics.

Author Contribution

Isaac Baidoo: conceptualization, writing – original draft. Heidi Abrahamse: funding acquisition, writing – review and editing, project administration, supervision. Blassan P. George: funding acquisition, writing – review and editing, project administration, supervision.

Funding

This research was supported by the South African Research Chairs initiative, funded by the Department of Science and Technology and the National Research Foundation (NRF) of South Africa [Grant No. 98337], as well as by the South African Medical Research Council [Grant No. SAMRC EIP007/2021]. Additional funding was received from the NRF Research Development Grants for Y‐Rated Researchers [Grant No. 137788], the Council for Scientific and Industrial Research (CSIR)‐African Laser Centre (ALC) (Grant No. HLHA26X Task ALC‐R001), National Laser Centre (NLC), and the University Research Committee (URC).

Conflicts of Interest

The authors confirm that the research was carried out without any involvement in commercial or financial relationships that could be perceived as a possible conflict of interest.

Declaration of Generative AI and AI‐assisted Technologies

During the preparation of this work, the authors used ScholarAi to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Biographies

Isaac Baidoo is a PhD candidate in Health Science (Biomedical Science–Research) at the Laser Research Centre, University of Johannesburg, South Africa, where he previously completed his Master's degree with distinction. His research focuses on photodynamic therapy, cancer nanomedicine, natural product‐based therapeutics, drug delivery systems, and precision oncology. His work integrates natural compounds, nanotechnology, and light‐based therapeutic strategies to develop innovative approaches for cancer treatment.

Heidi Abrahamse is Professor and Director of the Laser Research Centre at the University of Johannesburg, South Africa, and holds the South African Research Chairs Initiative (SARChI) Chair in Laser Applications in Health. Her research focuses on photobiomodulation, photodynamic therapy, stem cell biology, molecular cell biology, and regenerative medicine. She has authored more than 500 peer‐reviewed publications and is internationally recognized for her contributions to laser‐based biomedical research, photomedicine, and translational health sciences.

Blassan P. George is a Professor at the Laser Research Centre, University of Johannesburg, South Africa. His research focuses on cancer photodynamic therapy, and medicinal plants. His work integrates natural products, molecular biology, and nanotechnology to advance innovative therapeutic strategies for cancer. He has authored more than 180 peer‐reviewed publications and has made significant contributions to the fields of photomedicine, natural product research, and cancer therapeutics.

Data Availability Statement

No new datasets were generated or analyzed during the current study; therefore, data sharing is not applicable.