Advances in BODIPY Derivatives for Antibacterial Phototherapy

ABSTRACT

The escalating threat posed by antibiotic‐resistant bacteria and biofilm‐associated infections has driven increasing interest in non‐antibiotic antibacterial strategies. Antibacterial phototherapy (PT), including photodynamic therapy (PDT) and photothermal therapy (PTT), has attracted considerable attention owing to its spatiotemporal controllability, broad‐spectrum antibacterial activity, and low propensity for inducing drug resistance. Boron‐dipyrromethene (BODIPY) dyes, featuring exceptional structural tunability and favorable photophysical properties, have emerged as versatile scaffolds for the construction of antibacterial phototherapeutic systems. Through molecular engineering strategies including cationization, heavy‐atom incorporation, and π‐conjugation extension, combined with nanoassembly approaches, both the excited‐state processes of BODIPY and its interactions with bacterial interfaces can be precisely regulated. Integration into diverse nanoplatforms further improves aqueous dispersibility, biological stability, and accumulation at bacterial or biofilm interfaces, thereby enhancing reactive oxygen species (ROS) generation or enabling photothermal effects to achieve PDT, PTT, or synergistic antibacterial therapy. This review systematically summarizes the design strategies and structure‐activity relationships of BODIPY‐based antibacterial phototherapy reported over the past five years, covering molecular engineering of small‐molecule photosensitizers and nanoplatforms, bacterial targeting and carrier design, and discussing the challenges and future perspectives associated with clinical translation, particularly in terms of biosafety and targeted delivery.

This review systematically summarizes the design strategies and structure‐activity relationships of BODIPY‐based antibacterial phototherapy, covering molecular engineering of small‐molecule photosensitizers and nanoplatforms, bacterial targeting and carrier design, and discussing the challenges and future perspectives associated with clinical translation, particularly in terms of biosafety and targeted delivery.

1. Introduction

Bacterial infections have long represented a central challenge to global public health systems, with their high morbidity and mortality rates continuing to impose substantial burdens on healthcare resource allocation, socioeconomic development, and human health [1]. Since the mid‐20^th century, the widespread application of antibiotics in clinical treatment and disease prevention has significantly reduced infection‐related mortality; however, the sustained selective pressure has concomitantly accelerated the emergence and dissemination of bacterial resistance, rendering antimicrobial resistance (AMR) one of the most formidable public health threats of the 21^st century [2]. It is estimated that approximately 4.95 million deaths globally were associated with AMR in 2019, of which 1.27 million were directly attributable to drug‐resistant bacterial infections [3]. Extensive clinical and epidemiological evidence further indicates that the incidence and mortality risk of resistant infections continue to rise, with predictive models suggesting that the associated mortality burden may intensify further by 2050 [4, 5]. More critically, the complex resistance mechanisms exhibited by multidrug‐resistant (MDR) bacteria, particularly Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Acinetobacter baumannii (A. baumannii), together with their capacity to form biofilms, have further exacerbated the therapeutic limitations of conventional antibiotics [6, 7]. To address these escalating challenges, various non‐antibiotic therapeutic strategies have been actively explored. Among these, phototherapy has emerged as a particularly promising approach, offering spatiotemporal controllability, rapid and efficient bactericidal effects, and a low risk of inducing resistance [8, 9]. In particular, research on BODIPY‐based photosensitizers in antibacterial phototherapy has expanded substantially in recent years. Numerous reviews and experimental studies have documented advances in the molecular design and antibacterial applications of this class of photosensitizers, reflecting the promising potential of this platform in addressing the AMR crisis [10].

Based on the primary energy conversion pathways during treatment, antibacterial phototherapy is mainly classified into photodynamic therapy (PDT) and photothermal therapy (PTT) [11]. In PDT, photosensitizers are excited to the singlet excited state (S₁) upon irradiation at specific wavelengths and subsequently undergo intersystem crossing (ISC) to the triplet state (T₁). The triplet‐state photosensitizer can then generate reactive oxygen species (ROS) through two distinct mechanisms: The Type I mechanism involves electron transfer between the photosensitizer and biological substrates, producing superoxide anion radicals (•O₂ ⁻), and hydroxyl radicals (•OH); the Type II mechanism transfers the excited‐state energy to ground‐state molecular oxygen, generating singlet oxygen (¹O₂) [12, 13]. These ROS achieve rapid bacterial killing through multiple synergistic pathways, including oxidation of bacterial cell membrane lipids, disruption of DNA structures, and inactivation of essential enzymes [12]. In contrast, PTT relies on the conversion of absorbed light energy into heat through non‐radiative relaxation pathways. The resulting localized hyperthermia (typically >43 °C) induces bacterial protein denaturation, loss of cell membrane fluidity, and metabolic dysfunction, thereby achieving broad‐spectrum bactericidal effects independent of molecular oxygen [14, 15]. Notably, many photosensitizer systems have achieved dual‐modal synergistic therapy, demonstrating superior efficacy compared to single‐mode treatments in complex infection scenarios, such as hypoxic microenvironments or dense biofilms.

1.1. Fundamental Principles of Antibacterial Phototherapy

The core of antibacterial phototherapy lies in the precise regulation and efficient conversion of photosensitizer excited‐state energy. According to the Jablonski energy diagram, upon photon absorption, a photosensitizer undergoes transition from the ground state (S₀) to S₁, subsequently dissipating energy through three competitive pathways: (i) radiative transition (fluorescence emission, S₁→S₀); (ii) ISC (S₁→T₁) followed by ROS generation via energy transfer or electron transfer; and (iii) non‐radiative decay converting to thermal energy [16]. For PDT, enhancing ISC efficiency is crucial, which is typically achieved through the introduction of heavy atoms (e.g., I, Br) to strengthen spin‐orbit coupling (SOC) or through the construction of charge‐transfer states. The relative contributions of Type I and II mechanisms depend on the redox potential of the photosensitizer, the triplet‐state energy level, and local oxygen concentration: Type I can effectively generate •OH and •O₂ ⁻ even under hypoxic conditions, although its quantum yield is generally lower than that of Type II; Type II relies on sufficient O₂ supply, and its singlet oxygen quantum yield serves as a core evaluation parameter for PDT efficacy [17]. In contrast, PTT requires maximization of non‐radiative decay channels, which can be achieved through the introduction of intramolecular motion units, construction of J‐aggregates, or optimization of charge‐transfer state geometries (Figure 1) [14, 18, 19]. In antibacterial applications, therapeutic efficacy is commonly assessed using parameters such as minimum inhibitory concentration (MIC), log reduction values, and biofilm eradication rates. It is important to emphasize that ROS possess extremely short lifetimes (nanosecond to microsecond scale) and limited diffusion radii (<20 nm); therefore, close proximity between the photosensitizer and bacterial membranes is essential for achieving efficient bactericidal effects [11, 20, 21].

FIGURE 1.

Molecular structure of BODIPY with eight functionalizable positions (left) and Jablonski energy diagram illustrating the photophysical mechanisms of antibacterial phototherapy, including PDT and PTT (right).

Among the numerous photosensitizer systems employed in antibacterial phototherapy, BODIPY has emerged as a representative photosensitizing platform with both molecular engineering and nanoengineering potential, owing to its excellent photophysical properties and high structural tunability (Figure 1) [22]. BODIPY was first synthesized by Treibs and Kreuzer in 1968 and was initially utilized primarily as a fluorescent probe for bioimaging studies [23]. Following the turn of the 21st century, with deepening understanding of its excited‐state regulation mechanisms, BODIPY has progressively expanded into the field of PDT, while research specifically targeting antibacterial applications has been concentrated mainly from 2015 to the present. Compared with conventional photosensitizers such as porphyrins and phthalocyanines, BODIPY exhibits a unique combination of advantages: (i) High molar extinction coefficients; (ii) Excellent photostability with strong resistance to photobleaching; (iii) A rigid π‐conjugated scaffold providing eight functionalizable positions for structural diversification; and (iv) tunable absorption wavelengths spanning the visible to the near‐infrared (NIR) region (Figure 1) [10, 22]. More importantly, the excited‐state energy dissipation pathways of BODIPY can be directionally switched from “fluorescence‐dominated” to “ROS generation” or “photothermal conversion” through molecular design, providing substantial design flexibility for constructing PDT, PTT, or dual‐modal synergistic antibacterial systems. Furthermore, the BODIPY scaffold can effectively overcome its inherent hydrophobicity and aggregation‐caused quenching (ACQ) in aqueous solutions through strategies such as cationic modification [24, 25], amphiphilic assembly, or covalent anchoring to polymers and framework materials [26, 27, 28, 29], thereby maintaining stable photosensitizing activity in complex physiological environments.

1.2. Current Challenges

Despite the tremendous application potential demonstrated by the BODIPY photosensitizing platform, its practical implementation in antibacterial phototherapy still faces several critical challenges: (i) ACQ effect: Hydrophobic BODIPY molecules tend to undergo π–π stacking aggregation in aqueous solutions, resulting in significant reduction of fluorescence and ROS generation capacity, thereby limiting their effectiveness in physiological environments. (ii) Limited tissue penetration depth: The absorption wavelengths of most BODIPY derivatives are concentrated in the visible region, where light penetration depth in biological tissues is typically <5 mm, rendering treatment of deep soft tissue infections difficult; therefore, development of NIR‐responsive BODIPY photosensitizers remains an urgent direction requiring breakthrough. (iii) Oxygen dependence limitations: conventional Type II photosensitizers exhibit compromised efficacy in the hypoxic microenvironments commonly encountered in bacterial infections (e.g., abscesses, deep biofilm layers), necessitating the development of Type I mechanism‐dominated or PDT/PTT synergistic oxygen‐independent strategies [17]. (iv) Biofilm penetration barriers: The dense three‐dimensional structure formed by the extracellular polymeric substance (EPS) matrix in mature biofilms severely impedes photosensitizer diffusion and retention, making deep eradication difficult to achieve through phototherapy alone [30]. (v) Clinical translation difficulties: Multiple challenges persist, including light dose standardization, portable light source development, long‐term biosafety assessment, and large‐scale pharmaceutical manufacturing; Currently, no BODIPY‐based antibacterial phototherapy products have received clinical approval [31]. Addressing these issues requires innovative integration across multiple dimensions, including molecular design, nano‐delivery systems, targeting strategies, and multimodal synergistic approaches.

1.3. Scope and Organization of this Review

In light of the aforementioned opportunities and challenges, this review aims to systematically summarize research advances in BODIPY‐based antibacterial phototherapy over the past five years. The review first elucidates molecular‐level modification strategies for BODIPY, including heavy atom/heavy‐atom‐free induced ISC regulation, non‐radiative decay pathway enhancement, and NIR shift design, revealing the structure‐activity relationships governing excited‐state energy dissipation. Subsequently, the focus shifts to molecularly engineered BODIPY antibacterial systems, encompassing cationization and alkyl chain engineering, microenvironment‐responsive smart activation (pH, enzymatic cleavage, NO release), and supramolecular self‐assembly strategies, discussing how to optimize photosensitizer‐bacteria interfacial interactions. The review then discusses framework‐ and polymer‐based BODIPY platforms, including covalent organic frameworks (COFs) and functional polymers (chitosan, gelatin, PVA, etc.), demonstrating how scaffold immobilization can overcome ACQ and enable diversified material morphologies for various applications. This is followed by a summary of organic‐inorganic hybrid BODIPY nanoplatforms, with emphasis on multi‐mechanistic synergistic enhancement in 2D transition metal carbides and nitrides (MXenes), metal oxide, and metal‐organic framework (MOF) composite systems. Finally, the review concludes with a comprehensive summary and provides perspectives on future research directions in this field, including NIR‐II photosensitizer development, immunomodulation, theranostic integration, and clinical translation pathways.

2. Modification Strategies for BODIPY Derivatives in Phototherapy

In the field of phototherapy research, BODIPY has been extensively employed in fluorescence imaging owing to its excellent photostability, favorable optical properties, and highly modifiable molecular structure, and has gradually been recognized as a promising photosensitizing molecular platform [22]. However, the excited‐state energy dissipation of the unmodified BODIPY core is typically dominated by radiative transitions. Although this characteristic endows BODIPY with high‐brightness fluorescence imaging capability, it establishes a strong competitive relationship with therapeutically relevant excited‐state processes in phototherapy applications: On one hand, the probability of ISC to the triplet state is limited, thereby attenuating the generation capacity of ROS including ¹O₂ and •O₂ ⁻ [32]; On the other hand, the restricted non‐radiative relaxation channels reduce photothermal conversion efficiency (PCE) [33]. Therefore, achieving the functional transformation of BODIPY from a “high fluorescence quantum yield dye” to an “efficient phototherapeutic agent” fundamentally relies on modulating its excited‐state energy dissipation pathways through molecular engineering approaches, thereby directing preferential allocation of light energy toward energy dissipation channels associated with PDT or PTT.

Toward this objective, multiple representative structural modification strategies have been developed for the BODIPY scaffold in recent years. One category of strategies primarily addresses the efficacy enhancement requirements of PDT: The introduction of halogens to induce the heavy atom effect enhances SOC, thereby weakening spin‐forbidden transitions and increasing the ISC rate, representing a classical approach for constructing efficient triplet‐state photosensitizers [34, 35]. Meanwhile, heavy‐atom‐free strategies based on intramolecular charge transfer (ICT), such as constructing orthogonal donor‐acceptor systems to induce spin‐orbit charge transfer ISC (SOCT‐ISC), have also been demonstrated to achieve high triplet‐state formation efficiency without relying on heavy atoms, providing a complementary paradigm for the design of efficient PDT molecules [36, 37]. Another category of strategies focuses on PTT performance optimization: by modulating intramolecular motion freedom and aggregation behavior to promote excited‐state energy dissipation through non‐radiative decay channels, PCE can be effectively enhanced [38, 39, 40]. Furthermore, addressing the requirements for deep tissue therapy, extension of the π‐conjugated system or construction of aza‐BODIPY structures can effectively narrow the HOMO‐LUMO energy gap, red‐shifting the absorption spectrum into the NIR biological window, thereby improving light penetration in deep tissues and expanding the application potential in deep‐seated infections and complex lesions [41]. The aforementioned synergistic modulation at the molecular level not only optimizes the antibacterial performance of BODIPY derivatives in single‐mode therapy, but also provides clear molecular design rationale for the construction of multi‐mechanistic synergistic antibacterial phototherapy systems.

2.1. Heavy‐Atom‐Induced and Heavy‐Atom‐Free ISC Engineering

For BODIPY dyes renowned for their intense fluorescence emission, the singlet‐to‐triplet transition is typically a low‐probability process due to spin‐forbidden effects. Consequently, how to effectively overcome this intrinsic limitation through molecular engineering approaches and achieve controllable enhancement of the ISC process has become a key challenge in constructing efficient photodynamic molecules [22, 32]. Toward this objective, two representative categories of ISC engineering strategies have been progressively developed for the BODIPY scaffold: one relies on the introduction of heavy atoms to enhance SOC; the other achieves structure‐driven heavy‐atom‐free ISC enhancement without introducing heavy atoms, through modulation of molecular orbital energy levels and electron distribution, optimization of donor‐acceptor unit configurations, and conformational orthogonalization. The following discussion will address these two strategies separately, with emphasis on elucidating the design significance of their excited‐state regulation mechanisms in photodynamic antibacterial systems.

The introduction of halogen atoms into the BODIPY scaffold to induce the heavy atom effect has long been recognized as one of the most direct and effective molecular design strategies for promoting ISC. The incorporation of heavy atoms can significantly enhance the SOC strength of the molecule, thereby effectively weakening the spin‐forbidden restriction in the S₁→T₁ transition, increasing the probability and rate of ISC occurrence, and further improving triplet‐state formation efficiency. Shi et al. constructed a series of BODIPY derivatives (BDP1‐BDP6) to systematically investigate the effects of different substituents (‐H, ‐I, ‐CHO, and ‐NO₂) and substitution positions on antibacterial photodynamic activity (Figure 2a) [34]. The study revealed that, the derivative with 2,6‐diiodo substitution and a phenyl group at the meso‐position (BDP3) exhibited the highest ROS generation efficiency, with ¹O₂ production capacity significantly superior to other derivatives (Figure 2b). In photodynamic antibacterial evaluation, BDP3 demonstrated exceptional inactivation activity against S. aureus (Figure 2c), with MIC as low as 10 nM, and effectively inhibited bacterial biofilm formation (Figure 2d). This study also revealed an important structure‐activity relationship: When weakly electron‐withdrawing groups were introduced on the phenyl ring (e.g., BDP5), ¹O₂ generation efficiency remained at relatively high levels; However, when strongly electron‐withdrawing groups were introduced (e.g., BDP6), ¹O₂ generation efficiency decreased significantly. This indicates that, the introduction of strongly electron‐withdrawing groups may attenuate the photoinduced electron transfer (PET) capability, thereby reducing ¹O₂ generation efficiency.

FIGURE 2.

(a) Chemical structures of BDP1‐BDP6. (b) ¹O₂ generation efficiency determined by the DPBF method. (c) Photodynamic antibacterial efficacy of BDP1‐BDP6 against S. aureus. (d) Inhibition of S. aureus biofilm formation by BDP3‐BDP5. Reproduced with permission [34]. Copyright 2022, Elsevier.

Building upon this foundation, subsequent studies have further provided more systematic elucidation of the applicable conditions and structural dependence of the heavy atom effect in BODIPY photodynamic systems from the perspective of coupling between molecular structure and excited‐state energy dissipation processes. Sen et al. conducted a comparative study of 2,6‐diiodo BODIPY and its π‐conjugation extended derivatives (BDP7‐BDP10), demonstrating that although the introduction of iodine atoms effectively promoted ISC through enhanced SOC, the singlet oxygen quantum yield actually decreased following π‐conjugation extension via Knoevenagel condensation to introduce pyridine‐vinyl groups at the 3,5‐positions (Figure 3b) [35]. This phenomenon was attributed to the fact that π‐conjugation extension, while achieving red‐shifting of the absorption spectrum, simultaneously enhanced non‐radiative relaxation, thereby attenuating excited‐state energy transfer to molecular oxygen. In photodynamic antibacterial activity evaluation against S. aureus, 2,6‐diiodo BODIPY achieved a 9.75 log reduction in colony counts at a concentration of 20 µM, whereas the π‐extended derivative exhibited significantly diminished antibacterial activity even at concentrations as high as 80 µM (Figure 3c). These results indicate that heavy atom‐induced ISC enhancement does not increase linearly with the degree of conjugation, but rather is synergistically constrained by multiple factors including molecular rigidity, energy level arrangement, and non‐radiative relaxation rates.

FIGURE 3.

(a) Chemical structures of BDP7‐BDP10. (b) ¹O₂ generation efficiency determined by the DPBF method. (c) Photodynamic antibacterial efficacy of BDP7‐BDP10 against S. aureus. Reproduced with permission [35]. Copyright 2023, Wiley.

Although heavy atom strategies can effectively enhance SOC and increase ISC probability, their potential dark toxicity and long‐term biosafety concerns in biological systems have prompted researchers to shift toward “heavy‐atom‐free” ISC enhancement strategies centered on molecular configuration modulation. This strategy no longer relies on exogenous heavy atoms, but instead improves triplet‐state formation efficiency through ICT‐based ISC enhancement mechanisms, such as introducing intramolecular charge transfer states, reducing the singlet‐triplet energy gap (ΔE _ST), or constructing SOCT‐ISC channels.

In this context, donor‐acceptor (D‐A or D‐A‐D) frameworks are commonly employed to introduce ICT and promote ISC through energy level matching and ΔE _ST reduction. Peng et al. designed a water‐soluble D‐A‐D type conjugated oligomer, BDP11, composed of cyclopenta‐dithio‐phene (CDT, donor) and BODIPY (acceptor) (Figure 4a) [36]. Density functional theory (DFT) calculations revealed that this molecule exhibits pronounced ICT characteristics and presents a small ΔE _ST (0.81 eV). This thermodynamically favorable energy gap effectively drives the ISC process, thereby enhancing ROS generation capacity. BDP11 is capable of simultaneously generating ¹O₂ and •O₂ ⁻, indicating that its ROS production process possesses both Type I and II mechanistic characteristics (Figure 4b). Concurrently, extension of the conjugated system narrows its HOMO‐LUMO bandgap to approximately 1.70 eV, on this basis, excited‐state energy is efficiently dissipated through non‐radiative relaxation channels, enabling BDP11 to exhibit a high PCE of 33.1% (Figure 4c). In antibacterial evaluation, this material demonstrated excellent bactericidal effects against E. coli, S. aureus, and C. albicans under 660 nm laser irradiation, with minimum bactericidal concentrations (MBC) of approximately 10 µg mL⁻¹ (Figure 4d). Thus, this system achieves synergistic distribution of excited‐state energy toward both ROS generation and thermal dissipation pathways, providing a molecular‐level design paradigm for PDT/PTT synergistic antibacterial therapy.

FIGURE 4.

(a) Illustration of the antibacterial mechanism of BDP11 through combined PDT/PTT treatment. (b) Detection of ¹O₂ and •O₂ ⁻ generation using SOSG and DHE fluorescent probes. (c) Photothermal conversion performance and PCE of BDP11. (d) Photodynamic antibacterial efficacy of BDP11 against E. coli, S. aureus, and C. albicans. Reproduced with permission [36]. Copyright 2021, American Chemical Society.

Although the introduction of ICT in planar D‐A configurations can effectively modulate the molecular energy gap, its photophysical behavior is often constrained by the energy gap law, whereby non‐radiative decay processes are significantly enhanced as the singlet energy level decreases, thereby exerting competitive inhibition on ISC. In contrast, geometry‐based modulation provides a new strategy for excited‐state transition pathways through the electronic coupling restrictions introduced by conformational orthogonalization, among which SOCT‐ISC is recognized as an important mechanism for achieving efficient triplet‐state generation in heavy‐atom‐free systems. Yang et al. constructed an orthogonal dyad BDP12 through covalent coupling of an aza‐BODIPY donor with a BODIPY acceptor (Figure 5a) [37]. DFT calculations revealed that the two chromophores adopt a nearly orthogonal torsional configuration (approximately 76°) (Figure 5b), resulting in “restricted coupling” characteristics in the electronic interactions between their frontier orbitals (Figure 5c). This orthogonal configuration leads to two independent absorption bands in the molecule, confirming the presence of significant steric hindrance between the two chromophores (Figure 5d). Within the theoretical framework of SOCT‐ISC, the orbital angular momentum changes accompanying the orthogonal charge transfer process can effectively enhance SOC, mechanistically promoting the S₁→T₁ intersystem crossing process. This design enables BDP12 to achieve efficient triplet‐state formation without heavy atom modification, with ROS generation capacity three times that of commercial ICG (Figure 5e), demonstrating excellent ¹O₂ generation ability and remarkable photodynamic antibacterial efficacy under NIR excitation.

FIGURE 5.

(a) Chemical structure of BDP12. (b) The optimized molecular structure of BDP12. (c) Molecular orbital diagrams of BDP12. (d) Absorption spectra of BDP12 in different solvents. (e) Comparison of ¹O₂ generation efficiency between BDP12 and ICG determined by the DPBF method. Reproduced with permission [37]. Copyright 2021, World Scientific.

In summary, from classical modification strategies relying on the heavy atom effect to enhance SOC, to structure‐driven modulation achieved through charge transfer and conformational orthogonalization, existing ISC regulation strategies have effectively optimized the excited‐state energy distribution of BODIPY photosensitizers at the molecular level. These approaches aim to maximize the conversion of excited‐state energy toward long‐lived triplet states and effectively drive the generation of ROS, including ¹O₂ and other ROS, through ISC channels.

2.2. Non‐Radiative Decay Pathways for Photothermal Enhancement

Although the aforementioned ISC regulation strategies have significantly improved ROS generation efficiency, bactericidal modes relying solely on ROS still face inherent efficacy limitations in hypoxic microenvironments (such as deep‐seated abscesses) or complex biological barriers including dense biofilms. To overcome this limitation, PTT has gradually attracted attention as a broad‐spectrum antibacterial strategy that operates independently of molecular oxygen and is dominated by physical thermal effects [14]. From the perspective of energy competition illustrated in the Jablonski energy diagram, excited‐state energy dissipation of photosensitizers encompasses, not only radiative transitions and ISC, but also direct conversion of light energy into thermal energy through non‐radiative relaxation channels. Therefore, from a molecular scale perspective, the core challenge in constructing efficient BODIPY photothermal agents lies in how to effectively suppress radiative transition processes and enhance internal conversion and vibrational relaxation rates, thereby enabling preferential dissipation of excited‐state energy as thermal energy through non‐radiative channels. Toward this objective, multiple strategies have been developed in recent years, primarily including: (i) Introduction of intramolecular rotor units with rotational degrees of freedom [38]; (ii) Construction of J‐aggregates favorable for non‐radiative decay through aggregation‐state engineering [39]; and (iii) Achievement of environment‐responsive excited‐state modulation through mechanically interlocked topological structures [40]. The following discussion will address each of these three strategies separately.

Triphenylamine (TPA), with its distinctive propeller‐shaped spatial configuration and strong electron‐donating capability, has been extensively introduced into BODIPY and its derivative systems to enhance non‐radiative transitions and improve PCE.

Sun et al. constructed a molecule (BDP13) coupling iodinated BODIPY with a triphenylamine group, which was co‐assembled with Pluronic F‐127 to form nanoparticles (BICF NPs) (Figure 6a) [38]. In this system, TPA serves dual functions: first, as a strong electron‐donating donor, it establishes a donor‐acceptor (D‐A) architecture with the electron‐deficient BODIPY core, inducing the formation of a twisted intramolecular charge transfer (TICT) state, thereby significantly red‐shifting the absorption spectrum and attenuating radiative transitions; Second, the propeller‐like configuration of TPA undergoes intense intramolecular rotation in the excited state, significantly accelerating non‐radiative relaxation through the intramolecular motion‐induced photothermy (iMIP) mechanism and efficiently converting light energy into thermal energy. Experimental measurements revealed that BICF NPs exhibited a PCE of 30.1% with excellent photothermal stability (Figure 6b). In a mouse subcutaneous abscess model, BICF NPs elevated the temperature of the abscess region to above 54° C within 5 min under 685 nm laser irradiation and maintained this temperature for 10 min (Figure 6c), effectively eradicating the infection and promoting wound healing through localized hyperthermia (Figure 6d).

FIGURE 6.

(a) Schematic illustration of the co‐assembly of BDP13 and F‐127 to prepare BICF NPs. (b) PCE and photothermal stability of BICF NPs. (c) Infrared thermal imaging of mouse subcutaneous abscess model under 685 nm laser irradiation. (d) Photographs of wound healing process in mice from different treatment groups. Reproduced with permission [38]. Copyright 2024, Elsevier.

Beyond molecular‐level rotor design, aggregate engineering provides an alternative effective approach for modulating excited‐state energy dissipation pathways. Unlike H‐aggregates, which cause fluorescence quenching and are unfavorable for phototherapy, J‐aggregates adopt a head‐to‐tail slipped stacking arrangement between molecules (Figure 7b), which not only significantly red‐shifts the absorption spectrum due to exciton coupling effects, but also fundamentally alters the excited‐state energy dissipation pathway, effectively promoting non‐radiative thermal relaxation. Bao et al. introduced an N‐nitrosamine group onto the aza‐BODIPY scaffold to develop a NIR J‐aggregate photothermal platform (BDP14) (Figure 7a) [39]. The introduction of the N‐nitrosamine group effectively suppressed intermolecular aromatic interactions, enabling BDP14 to preferentially form highly ordered J‐aggregates within PEG‐b‐PCL micelles. This study revealed the precise regulatory relationship between aggregation state and PCE: as the BDP14 loading in micelles increased, the degree of J‐aggregation progressively enhanced (Figure 7c), accompanied by a significant improvement in PCE. Under the highest loading condition (10 wt%), the compact molecular packing of J‐aggregates enabled nearly complete dissipation of excited‐state energy through non‐radiative thermal relaxation pathways, achieving a PCE as high as 73.6%. Under 808 nm laser irradiation, the temperature of the highly loaded micellar solution increased by approximately 30 °C within 10 min (Figure 7d).

FIGURE 7.

(a) Schematic illustration of the co‐assembly of BDP14 and PEG‐b‐PCL to prepare micellar nanoparticles. (b) Molecular packing configuration of BDP14 J‐aggregates from molecular dynamics simulation. (c) Absorption spectra of micelles with different BDP14 loading contents. (d) Photothermal heating curves of micelles with different loading contents (NP‐2, NP‐4, NP‐5) under 808 nm laser irradiation. Reproduced with permission [39]. Copyright 2022, Wiley‐VCH.

As an emerging molecular design strategy, mechanically interlocked molecules (MIMs) have been introduced to achieve dynamic control over excited‐state energy dissipation pathways. Sambucari et al. constructed a series of triaryl phosphonium‐based BODIPY‐[2]rotaxanes, revealing a highly environment‐dependent excited‐state modulation mechanism (Figure 8a) [40]. In organic solvents (monomolecular state), the brominated rotaxane undergoes efficient ISC, driving Type II photodynamic reactions to generate ¹O₂; However, upon self‐assembly into nanoparticles in aqueous phase (Figure 8b), ISC is suppressed in the aggregated state, and the excited‐state energy dissipation pathway shifts predominantly toward non‐radiative thermal relaxation, exhibiting high PCE and excellent photothermal stability (Figure 8c). This “environment‐responsive switch” mechanism enables the system to transition between photodynamic and photothermal modes according to the microenvironment, providing new insights for the design of intelligent phototherapeutic agents.

FIGURE 8.

(a) Molecular design of BDP15. (b) SEM image of spherical nanoparticles self‐assembled from rotaxanes in aqueous solution. (c) PCE measurement and photothermal stability evaluation of BDP15 nanoparticles. Reproduced with permission [40]. Copyright 2025, Wiley‐VCH.

In summary, whether through intramolecular motion modulation based on TPA rotors, utilization of exciton coupling and ordered stacking effects in J‐aggregates, or construction of environment‐responsive mechanically interlocked rotaxane topologies, the core principle of BODIPY photothermal agent design lies in the modulation of competitive relationships governing excited‐state energy dissipation within the Jablonski energy diagram. These strategies enhance non‐radiative decay channels while suppressing radiative transitions and ISC, thereby transforming excited‐state energy from what is conventionally regarded as passive “thermal loss” into an efficient, controllable, and molecular oxygen‐independent physical killing mechanism. This approach effectively circumvents the inherent limitations arising from the high oxygen dependence of PDT in hypoxic microenvironments.

2.3. Conjugation Extension, Aza‐BODIPY Design, and NIR Activation

The aforementioned ISC regulation and non‐radiative transition enhancement strategies have optimized the excited‐state energy dissipation distribution of BODIPY systems at the molecular level, improving their ROS generation capacity and PCE, respectively. However, although BODIPY exhibits excellent photophysical properties in the visible region (typically 500–550 nm), light penetration depth in tissues at this wavelength range is usually limited to the millimeter scale and is susceptible to interference from biological matrix autofluorescence, thereby significantly constraining its application in scenarios, such as deep soft tissue infections [42]. Therefore, extending the absorption and emission spectra of BODIPY into the NIR region to enhance tissue penetration and reduce background autofluorescence interference has become an important research direction in recent years [43].

The essence of spectral red‐shifting lies in narrowing the energy gap (ΔE _gap) between HOMO and LUMO. Based on this principle, multi‐level molecular modification strategies have been developed for the BODIPY scaffold, achieving NIR activation capability through energy level modulation and conjugation system engineering. Among these, π‐conjugation extension represents the most classical and widely applied red‐shifting strategy (Figure 9a). Through Knoevenagel condensation reactions to introduce electron‐rich aromatic substituents (such as styryl group) at the 3,5‐positions, the degree of π‐electron delocalization can be significantly enhanced while simultaneously reducing the HOMO‐LUMO energy gap, thereby effectively extending the absorption and emission wavelengths into the NIR region [35, 44, 45]. However, while achieving substantial red‐shifts, this strategy is often accompanied by increased molecular weight, decreased water solubility, and synthetic complexity. In contrast, aza‐BODIPY scaffold modification provides a more compact structural modulation approach. By replacing the carbon atom at the meso‐position with a nitrogen atom, the lone pair electrons of nitrogen stabilize the LUMO energy level, effectively narrowing the energy gap and achieving a spectral red‐shift of approximately 50–100 nm without appreciably increasing the conformational size or molecular weight (Figure 9b). Notably, this scaffold modification is typically accompanied by a decrease in fluorescence quantum yield; However, this characteristic is well aligned with the requirement for an increased proportion of nonradiative decay channels in PTT, thereby establishing a structural foundation for the construction of synergistic PDT/PTT antibacterial therapeutic systems [39, 46]. Furthermore, the aromatic ring fusion strategy, achieved through the introduction of fused units, such as thiophene or naphthalene as well as BODIPY dimerization and oligomerization, not only extends the π‐conjugation system to narrow the frontier orbital energy gap but, more critically, significantly enhances molecular planarity and rigidity, thereby effectively suppressing intramolecular rotation in the excited state and modulating nonradiative decay processes (Figure 9c). This “structural rigidification” characteristic enables this strategy to regulate ROS generation efficiency and photothermal conversion capability while achieving long‐wavelength absorption, providing a foundation for the design of multimodal phototherapy antibacterial systems [43, 47].

FIGURE 9.

Molecular design strategies for NIR activation of the BODIPY scaffold. (a) π‐Conjugation extension via Knoevenagel condensation at the 3,5‐positions. (b) aza‐BODIPY scaffold modification through meso‐carbon‐to‐nitrogen replacement. (c) Aromatic ring fusion strategy, including α‐ and β‐fused BODIPYs as well as BODIPY dimers and oligomers.

In summary, the NIR engineering of the BODIPY scaffold is not merely a simple red‐shift of the absorption wavelength, but rather a precise modulation of the molecular framework and electronic distribution. π‐Conjugation extension and aromatic ring fusion primarily narrow the HOMO‐LUMO energy gap by expanding the electron delocalization system, whereas aza‐BODIPY achieves regulation of frontier molecular orbital energy levels through heteroatom substitution. The complementary integration of these strategies not only broadens the NIR activation boundaries of the BODIPY platform, but also provides a valuable molecular design framework and guiding principles for the subsequent development of BODIPY photosensitizers that combine deep‐tissue photo responsiveness with high photosensitization efficiency.

3. Molecularly Engineered BODIPY Antibacterial Systems

Although the photophysical properties of BODIPY, including ROS generation and photothermal conversion, have been significantly optimized, its antibacterial efficacy is often limited by its targeting delivery capability and bio‐interface interaction efficiency in complex infection environments [48]. On the one hand, the ubiquitous negative charge barrier on bacterial surfaces, together with the dense structures of the outer membrane of Gram‐negative bacteria and biofilms, severely impedes the penetration, and retention of photosensitizers. On the other hand, the hypoxic, acidic, and inflammatory microenvironments commonly associated with infection foci impose limitations on a single bactericidal mechanism in certain clinical scenarios [49, 50, 51]. Consequently, molecular modification of BODIPY is no longer confined to the modulation of excited‐state processes, but has further expanded to emphasize the enhancement of bacterial interface delivery and penetration efficiency. Through meticulous structural design to strengthen recognition, adhesion, and directional accumulation on bacterial surfaces, the retention behavior at infection sites can be markedly improved, along with enhanced penetration into and disruption of biofilms [52, 53].

On this basis, this section categorizes, from the perspective of molecular function, three types of “function‐oriented” structural modification strategies for BODIPY: (i) Membrane‐targeting strategies based on electrostatic and hydrophobic interactions, which enhance bacterial membrane adhesion and promote biofilm disruption through alkyl chain engineering and cationic anchoring groups (such as quaternary ammonium salts, pyridinium, and triphenylphosphine) [24, 25, 26, 52, 54, 55, 56]; (ii) Targeting and responsive smart activation strategies, encompassing responsive activation triggered by acidic pH signals in the infection microenvironment [53, 57], active targeting mediated by specific recognition ligands (such as vancomycin and glycosyl ligands) [58, 59], and multimodal synergistic bactericidal strategies combining NO release‐based gas therapy with PTT [39, 60], aimed at improving therapeutic selectivity and achieving synergistic enhancement; and (iii) supramolecular self‐assembly and nano‐structured strategies, which leverage self‐assembly or nanocarriers to improve water solubility and biostability while enhancing lesion‐targeted delivery efficiency and amplifying localized phototherapeutic effects [27, 46, 61, 62]. The above classification facilitates a systematic understanding of how BODIPY derivatives address the dual challenges of bacterial drug resistance and the infection microenvironment through molecular design.

3.1. Cationic and Alkyl‐Chain‐Engineered BODIPY Derivatives

The unique properties of bacterial cell membranes represent the primary biological barrier to be considered in the design of photodynamic antibacterial agents. Whether it is the dense peptidoglycan layer and lipoteichoic acids on the surface of Gram‐positive bacteria or the lipopolysaccharides (LPS) on the outer membrane of Gram‐negative bacteria, the bacterial surface exhibits a pronounced negative potential [63, 64, 65]. In contrast, mammalian cell membranes are predominantly composed of zwitterionic lipids, resulting in a near‐neutral surface charge [66, 67]. By exploiting this charge disparity, the introduction of cationic groups into the BODIPY scaffold enables specific recognition and rapid electrostatic recruitment of bacteria. Moreover, cationization effectively suppresses ACQ of photosensitizers in physiological media by enhancing aqueous dispersibility and electrostatic repulsion [24, 56, 68]. On this basis, further modulation of molecular amphiphilicity through alkyl chain length and hydrophobic segments endows the photosensitizer with the ability to penetrate the lipid bilayer of bacterial membranes [69, 70, 71].

Quaternary ammonium salts (QAS) represent the most classic and highly effective cationic modification strategy. Their permanent positive charge centers, not only anchor to bacterial surfaces, but also disrupt the osmotic balance of cell membranes, leading to intracellular content leakage and, thereby achieving synergistic “contact killing” and photodynamic bactericidal effects. Wang et al. constructed a trimethylamine salt‐modified cationic BODIPY (BDP16‐TMA) (Figure 10a) [24]. Comparative experiments demonstrated that neutral or negatively charged analogues failed to adsorb effectively onto bacterial surfaces, whereas BDP16‐TMA nanoparticles rapidly adsorbed onto the surfaces of both S. aureus and E. coli (Figure 10b). This intimate bio‐interface contact dramatically shortened the diffusion distance of ¹O₂, enabling direct oxidation of membrane lipids and membrane proteins, which effectively inhibited biofilm formation and eradicated pre‐established biofilm structures (Figure 10c). However, in complex infection microenvironments, single, or dual positive charges, are often insufficient to simultaneously satisfy the dual requirements of “stable dispersion in physiological media” and “penetration through multilayered barriers”, thereby prompting the development of polycationic strategies. Xiao et al. designed and synthesized a series of thieno[3,2‐b]thiophene‐fused BODIPY derivatives (I₁‐I₄, II₁‐II₄) bearing multiple quaternary ammonium salts on the meso‐phenyl group, with each molecule carrying four quaternary ammonium groups through two symmetrical side chains (Figure 11a) [25]. The polycationic modification endowed the compounds with remarkable anti‐aggregation properties, maintaining a well‐dispersed monomeric state in solution. DFT calculations revealed that, thieno[3,2‐b]thiophene fusion significantly extended the π‐conjugation system, leading to a substantial reduction in the HOMO‐LUMO energy gap compared to the reference compound (Figure 11b). All compounds exhibited strong absorption at 650 nm, with I₁ and II₁ achieving ¹O₂ quantum yields as high as 0.52 and 0.46, respectively. Under 650 nm laser irradiation, I₁ and II₁ displayed MICs against S. aureus as low as 4 µg mL⁻¹ and achieved >99.9% photodynamic bactericidal efficiency at a concentration of 32 µg mL⁻¹ (Figure 11c). Furthermore, the polycationic architecture conferred outstanding antibiofilm activity: I₁ achieved a 95.37% inhibition rate against mature S. aureus biofilms under light irradiation (Figure 11d), and SEM imaging together with nucleic acid leakage assays (OD₂₆₀) further confirmed its bactericidal mechanism through disruption of bacterial membrane integrity leading to intracellular content efflux (Figure 11e).

FIGURE 10.

(a) Schematic illustration of the self‐assembly process and the photodynamic antibacterial performance of BDP16‐TMA NPs. (b) SEM images of S. aureus without any treatment and those treated with the BDP16 NPs or BDP16‐TMA NPs under green light irradiation. (c) CLSM images of the biofilms of S. aureus treated with the BDP16 NPs or BDP16‐TMA NPs and stained with SYTO and Pl with/without green light irradiation. Reproduced with permission [24]. Copyright 2022, Royal Society of Chemistry.

FIGURE 11.

(a) Structures of BDP17 (I₁‐I₄, II₁‐II₄). (b) FMOs of compounds I₁, I₃, II₁, and II₃. (c) Agar plate images showing the concentration‐dependent killing of S. aureus by compounds I₁ and II₁ at 0, 4, 8, 16, and 32 µg mL⁻¹ concentrations under 10 J cm⁻² light irradiation. (d) Representative images showing crystal violet staining of mature S. aureus biofilms treated with compounds I₁ and II₁ at 0, 4, 8, 16, and 32 µg mL⁻¹ concentrations under 10 J cm⁻² light irradiation. (e) Representative SEM images (top) and corresponding higher magnification images (bottom) of S. aureus treated with compounds I₁ and II₁ at a concentration of 32 µg mL⁻¹ under 10 J cm⁻² light irradiation. Reproduced with permission [25]. Copyright 2025, Elsevier.

Reliance solely on electrostatic adsorption remains insufficient to fully overcome the “physical barriers” constructed by the outer membrane of Gram‐negative bacteria and dense biofilms. To achieve the leap from “surface adsorption” to “membrane penetration,” an amphiphilic design featuring the synergy of a “cationic head‐hydrophobic tail” is particularly critical. Moderately hydrophobic tail chains (such as C8‐C12 alkyl chains) can insert into the lipid bilayer via van der Waals interactions, facilitating the anchoring and transmembrane transport of photosensitizers across bacterial membranes. Kocak et al. reported a representative dicationic amphiphilic BODIPY molecule (BDP18) [26], which ingeniously combined the strong electrostatic directing capability of dual quaternary ammonium head groups with the membrane insertion ability of C12 alkyl chains (Figure 12a). Experiments demonstrated that, this amphiphilic architecture not only endowed the molecule with broad‐spectrum antibacterial activity (MIC values of 4 and 16 µg mL⁻¹ against S. aureus and E. coli, respectively), but also imparted surfactant‐like membrane disruption characteristics, enabling effective penetration and eradication of recalcitrant S. epidermidis biofilms, with a minimum biofilm eradication concentration (MBEC) as low as 16 µg mL⁻¹ (Figure 12b). These results illustrate that in overcoming biofilm barriers, when charge accumulation alone proves inadequate, synergistic enhancement of electrostatic capture, and hydrophobic membrane insertion must be achieved through precise modulation of the hydrophilic‐lipophilic balance (HLB).

FIGURE 12.

(a) Structure and design factors of BDP18. (b) Crystal violet assay to assess the antibiofilm activity of BDP18 against S. epidermidis ATCC 12228 and S. epidermidis YT‐169a. Reproduced with permission [26]. Copyright 2023, American Chemical Society. (c) Schematic illustration of preparation and antibacterial application of BDP19 NPs. (d) Photographs of bacterial colonies (left) and SEM images (right) of S. aureus treated with PBS or BDP19 NPs in dark and light conditions. Reproduced with permission [55]. Copyright 2022, American Chemical Society.

Beyond quaternary ammonium salts, positively charged pyridinium and triphenylphosphonium (TPP⁺) cations have also been widely incorporated into the BODIPY scaffold to construct highly efficient cationic antibacterial photosensitizers. Among these, TPP⁺, as a classic lipophilic cation, can traverse the lipid bilayer driven by membrane potential and selectively accumulate in regions of high negative charge density, making it a longstanding tool for mitochondria‐targeted imaging and therapeutic systems. In antibacterial photodynamic therapy, TPP⁺ can similarly exploit the negative surface charge of bacterial cell envelopes and the transmembrane potential difference to enhance the adhesion and accumulation of photosensitizers at the bacterial interface, thereby promoting their penetration through bacterial envelopes. Wen et al. reported a photosensitizing molecule incorporating a TPP⁺ cation at the meso‐position of an iodinated BODIPY core, which was further self‐assembled into nanoparticles (BDP19 NPs) (Figure 12c) [55]. This system combined the strong electrostatic adsorption capability mediated by TPP⁺ with the heavy‐atom effect induced by iodine atoms, significantly enhancing accumulation on bacterial surfaces while ensuring efficient singlet oxygen generation. Experimental results demonstrated that BDP19 NPs exhibited a MIC as low as 0.3 µg mL⁻¹ against S. aureus under light irradiation and were capable of effectively penetrating mature biofilms and markedly promoting the healing of infected wounds, highlighting the synergistic advantages of lipophilic cations and PDT in antibacterial applications (Figure 12d).

Regarding pyridinium modification, Lin et al. systematically investigated the structure‐activity relationships of pyridinium groups introduced at the meso‐position of the BODIPY core, with a particular focus on comparing the effects of different linkage positions (ortho, meta, and para) and various alkyl substitutions on photophysical properties and antibacterial activity (Figure 13a) [56]. The study revealed that the linkage position of the pyridinium cation significantly influenced the singlet oxygen quantum yield and antibacterial efficacy of the photosensitizer by modulating PET, molecular aggregation behavior, and bacterial uptake efficiency. Specifically, the para‐pyridinium derivative exhibited a markedly reduced fluorescence quantum yield due to a strong PET effect, while the ortho‐pyridinium derivative displayed poor water solubility and bacterial uptake owing to the burial of the cationic moiety within the hydrophobic BODIPY scaffold. In contrast, meta‐pyridinium modification effectively suppressed the PET process and avoided structural burial of the cationic site while maintaining favorable aqueous compatibility, thereby achieving highly efficient antibacterial photodynamic activity (Figure 13b). Among the derivatives, the methylated meta‐pyridinium compound (BDP22) exhibited outstanding broad‐spectrum photodynamic antibacterial activity under light irradiation, with MIC values as low as 0.63, 1.25, 0.63, and 0.63 µM against S. aureus, E. coli, C. albicans, and methicillin‐resistant S. aureus (MRSA), respectively (Figure 13c).

FIGURE 13.

(a) Structures of meso‐(pyridinium) BODIPY photosensitizers BDP20‐BDP24. (b) Fluorescence microscopy images of C. albicans preincubated with DCFH‐DA and treated with various concentrations of BDP22 under light irradiation. (c) Photodynamic inactivation of S. aureus, E. coli, C. albicans, and MRSA incubated with BDP20‐BDP24 under light irradiation. Reproduced with permission [56]. Copyright 2021, American Chemical Society.

To systematically compare the differential roles of targeted recognition and electrostatic adsorption strategies in antibacterial photodynamic therapy, Wen et al. designed and compared BODIPY derivatives bearing either a phenylboronic acid (PBA) group or a pyridinium cation (Figure 14a) [52]. The study found that the pyridinium cation‐modified BDP25 exhibited potent broad‐spectrum antibacterial activity against both S. aureus and E. coli, attributable to its strong electrostatic interactions with negatively charged regions on bacterial surfaces, while its amphiphilic structure further disrupted bacterial membrane integrity (Figure 14b). In contrast, the receptor recognition‐based PBA strategy, although capable of specifically binding to Gram‐positive bacteria (MIC = 0.3 µM), was virtually ineffective against Gram‐negative bacteria (MIC >25 µM), revealing the inherent limitations of purely targeted recognition strategies in overcoming the outer membrane barrier of Gram‐negative bacteria (Figure 14c). This comparison further substantiated the unique advantages of electrostatic adsorption‐based cationic strategies in broad‐spectrum antibacterial photodynamic therapy and biofilm eradication.

FIGURE 14.

(a) Structures of four BODIPY photosensitizers: BDP25, BDP26, BDP27, and BDP28. (b) Interactions between the PBA‐functionalized BODIPYs and teichoic acid/LPS of bacteria via the borate ester covalent bond, as well as the electrostatic interactions between the Py cation‐functionalized BODIPYs and the negatively charged membranes of bacteria. (c) In vitro antibacterial activities of four BODIPYs at different concentrations against S. aureus and E. coli under green light irradiation. Reproduced with permission [52]. Copyright 2023, Royal Society of Chemistry.

In summary, the synergistic modulation of cationization (such as quaternary ammonium salts, triphenyl phosphonium, and pyridinium) and alkyl chain engineering provides an efficient and versatile molecular design strategy for enabling BODIPY photosensitizers to traverse bacterial membrane barriers and penetrate deeply into biofilms. Compared with targeting strategies that, rely solely on receptor recognition, this charge‐ and amphiphilicity‐regulated system demonstrates superior membrane penetration capability and broad‐spectrum antibacterial activity in Gram‐negative bacteria and mature biofilm models. However, positive charge modification may introduce nonspecific adsorption, leading to potential cytotoxicity or hemolysis risks. Moreover, sole reliance on electrostatic adsorption is inadequate for precisely addressing the dynamically changing infection microenvironment (such as, pH gradients, hypoxia, and inflammatory mediators). Therefore, advancing from “interfacial enrichment” to infection‐triggered selective activation and ligand‐mediated active targeting has emerged as an important direction for future research.

3.2. Targeting and Responsive BODIPY Derivatives

To address the off‐target toxicity and insufficient microenvironmental adaptability of conventional cationic photosensitizers, the design of BODIPY‐based antibacterial systems has progressively shifted in recent years from “electrostatically driven passive delivery” toward synergistic strategies integrating infection microenvironment responsiveness with bacteria‐specific recognition. Through the incorporation of microenvironment‐responsive mechanisms (such as pH triggering and charge reversal), photosensitizing activity can be switched “on demand” concurrent with bacterial accumulation, thereby minimizing nonspecific damage to normal tissues [53, 57]. By conjugating specific recognition ligands (such as vancomycin and glycosyl ligands), active recognition and directional anchoring to pathogens can be achieved, significantly enhancing targeting precision [58, 59]. Concurrently, the integration of photothermal or gas therapy molecules further enables multidimensional synergy encompassing bacterial killing, biofilm eradication, and inflammation modulation, offering novel design rationales for the construction of efficient, and safe anti‐infection phototherapeutic systems [39, 60].

3.2.1. pH‐Responsive Activation

Bacteria continuously produce organic acids, such as lactic acid and acetic acid during metabolism, which, combined with restricted diffusion within biofilms, creates a markedly acidic microenvironment at infection foci and within biofilm interiors (pH typically ranging from 4.5 to 6.6), significantly lower than normal physiological conditions [72, 73, 74]. Exploiting this disparity, researchers have developed pH‐responsive antibacterial photosensitizing systems. The core design rationale is as follows: Under neutral physiological conditions, the fluorescence and ROS generation of the photosensitizer are substantially suppressed to minimize nonspecific damage to normal tissues; upon entering the acidic microenvironment, the system achieves on‐demand activation and in situ amplification of photosensitizing activity through protonation‐induced charge alterations, conformational/aggregation state transitions, or carrier disassembly. This strategy significantly enhances the eradication efficiency against deep‐seated bacteria and biofilms while maintaining biosafety. Liang et al. constructed an acid‐triggered nanoplatform, IBPAAs, as a representative demonstration of this concept [53]. This system co‐assembled the BODIPY derivative BDP29, bearing diethylamino side chains, with the amphiphilic block copolymer POEGMA‐b‐PDEAEMA. Under neutral physiological conditions, BDP29 underwent fluorescence quenching due to PET, whereas upon entering an acidic environment, protonation of the diethylamino groups effectively attenuated the PET process, restoring excited‐state radiative transitions and ISC, thereby significantly enhancing ROS generation (Figure 15a). This “molecular switch” and “interfacial enrichment” operated synergistically within a single platform: Protonation of the copolymer under acidic conditions markedly elevated the zeta potential of the nano assembly surface, facilitating adsorption onto negatively charged bacterial surfaces and improving local retention. Concurrently, the system exhibited pronounced structural and photophysical responses between pH 7.4 and 5.5: the particle size increased from approximately 400 to 1000 nm (Figure 15b), fluorescence underwent an “off‐on” switch, and the singlet oxygen quantum yield increased from 0.054 to 0.14 (Figure 15c). These changes collectively enabled highly efficient photodynamic eradication of S. aureus and its biofilms by IBPAAs.

FIGURE 15.

(a) Schematic diagram for the preparation of the nanoplatform IBPAAs and its photodynamic antibacterial process. (b) Size distribution and TEM images of IBPAAs assemblies at pH = 7.4 (left) and pH = 5.5 (right). (c) Time‐dependent DPBF absorbance changes of IBPAAs assemblies under light irradiation at different pH conditions. Reproduced with permission [53]. Copyright 2022, Royal Society of Chemistry.

Beyond attenuating PET via protonation to restore photosensitizing activity, an alternative strategy involves the incorporation of a photoacid generator to achieve pH‐jump‐driven cascade release. Lu et al. reported BCNBA@ZIF, in which the photoacid generator ortho‐nitrobenzaldehyde (o‐NBA) initiates a series of “domino”‐type cascade effects [57]. Upon blue light irradiation, o‐NBA undergoes a photochemical reaction that releases protons, inducing an abrupt local pH decrease from 8.5 to 6.3. This pH jump triggers the disintegration of the ZIF‐8 shell, thereby enabling the synergistic co‐release of the BODIPY‐caffeic acid conjugate (BDP31) and Zn²⁺. This process is accompanied by sustained ¹O₂ generation, achieving multi‐mechanistic synergy between chemical bacteriostasis and PDT. The key innovation of this system lies in the utilization of a photoacid generator to convert the conventional acid‐responsive release of MOFs from a passive response into a spatiotemporally controllable, light‐triggered process (Figure 16a). In antibacterial assays, BCNBA@ZIF subjected to blue LED irradiation exhibited an inhibitory effect against E. coli nearly comparable to that of the clinical antibiotic ampicillin, demonstrating a characteristic “dark‐inert/light‐activated” photoresponsive antibacterial profile (Figure 16b).

FIGURE 16.

(a) Structures of BDP30 and BDP31, and schematic illustration of the synthesis of BCNBA@ZIF nanoparticles and their light‐driven “domino” antibacterial mechanism. (b) Photographs of plate colony counting of E. coli treated with blank control, BNBA@ZIF, BCNBA@ZIF, and Ampicillin Na under blue LED irradiation and dark conditions. Reproduced with permission [57]. Copyright 2020, American Chemical Society.

The aforementioned studies demonstrate that pH‐responsive strategies enable precise spatiotemporal regulation of photosensitizing activity, whether through polymer assemblies that passively respond to acid produced by bacterial metabolism (IBPAAs) or metal‐organic frameworks that achieve active light‐induced acid generation via a photoacid generator (BCNBA@ZIF) [53, 57]. Overall, pH‐responsive activation provides a “dark‐inert/light‐activated” regulatory paradigm for BODIPY‐based antibacterial systems: By tightly coupling photosensitizing activity with the acidic characteristics of the infectious microenvironment, these systems exhibit negligible toxicity in normal tissues, while selectively activating bactericidal effects within the acidic microenvironment of infected foci. In future developments, addressing the spatiotemporal heterogeneity of pH at infection sites and the physiological buffering effects will be critical for advancing this strategy toward broader generalizability and clinical translatability.

3.2.2. Specific Bacterial Targeting Ligands

Although microenvironment‐responsive strategies can facilitate the accumulation and activation of photosensitizers at infection sites to a certain extent, their action remains predominantly “passively triggered” and faces two critical bottlenecks. First, stimuli signals such as pH and ROS are often not strictly confined to the core of the lesion, potentially leading to nonspecific retention in surrounding tissues. Second, in deep‐seated infections or within the interior of mature biofilms, reliance solely on diffusion and environmental triggering is often insufficient to achieve adequate penetration and effective retention. The study by Wen et al. has preliminarily demonstrated the selective enrichment capability of receptor recognition‐based targeting strategies (e.g., PBA) toward Gram‐positive bacteria, while simultaneously revealing the inherent limitations of this approach in overcoming the outer membrane barrier of Gram‐negative bacteria [52]. Based on this, incorporating specific recognition ligands onto BODIPY or the surface of its nanostructured assemblies to achieve active recognition and targeted anchoring via pathogen surface molecular markers has gradually become an important strategy for enhancing targeting precision and expanding the therapeutic safety window [58, 59].

For MRSA, Sun et al. developed vancomycin (VAN)‐functionalized multifunctional nanoparticles (BDPV), in which a synergistic combination of “ligand recognition” and “microenvironment responsiveness” enabled targeted enrichment at bacteria/biofilms and thereby potentiated phototherapy [59]. In this system, VAN was covalently conjugated to DSPE‐PEG2000 via an amide linkage, while a tertiary amine modified BODIPY derivative capable of both PDT and PTT was encapsulated (Figure 17a). VAN specifically recognizes the D‐Ala‐D‐Ala motif of peptidoglycan precursors in the cell wall of Gram‐positive bacteria, thereby enhancing nanoparticle anchoring and local accumulation on MRSA; meanwhile, the mildly acidic infection milieu, particularly within biofilms, induces protonation of the tertiary amines on the BODIPY derivative, triggering a surface charge reversal from negative to positive and further strengthening affinity to the negatively charged bacterial membrane through electrostatic attraction. In vitro assays confirmed that BDPV exhibited a MIC of 80 µg mL⁻¹ against MRSA, achieving 91.7% growth inhibition at this concentration, and displayed pronounced clearance of mature biofilms. Collectively, combining ligand‐mediated active recognition with microenvironment‐triggered charge reversal can effectively improve photosensitizer enrichment and penetration at the bacteria/biofilm interface, thereby amplifying the synergistic bactericidal efficacy of PDT and PTT.

FIGURE 17.

(a) Schematic illustration of the preparation of nanoparticle BDPV. Reproduced with permission [59]. Copyright 2025, Elsevier. (b) Chemical structures of BDP33 and BDP34. Reproduced with permission [58]. Copyright 2024, MDPI.

For Gram‐negative bacteria, the barrier imposed by the LPS‐rich outer membrane markedly impedes photosensitizer penetration, making it a key challenge to enhance interfacial accumulation and short‐range interactions at the bacterial surface. Carbohydrate ligands can selectively recognize bacterial surface lectins, thereby participating in bacterial adhesion processes, and are considered a viable tool to improve the surface residence of photosensitizers. Gangemi et al. synthesized two oligophenylene ethynylene (OPE)‐based, multivalent BODIPY‐galactose conjugates (BDP33/ BDP34) [58], which integrate two BODIPY chromophores within a single molecular platform and decorate the periphery with three galactose units to probe the impact of glycosylation on antibacterial activity (Figure 17b). Experimental results showed that both compounds exhibited higher sensitivity toward Gram‐negative bacteria. Notably, the antibacterial activity of BDP34 after quaternization was comparable to that of BDP33, without the anticipated cationization‐driven enhancement, suggesting that multivalent galactose‐mediated lectin recognition and bacterial‐surface enrichment may be the dominant contributors in this system rather than simple electrostatic adsorption. This work highlights a design concept in which multivalent carbohydrate ligands facilitate enrichment on Gram‐negative bacterial surfaces, providing an expandable molecular framework for the further development of targeted photosensitizers.

Antimicrobial peptides (AMPs) exploit cationic, amphipathic sequences to engage anionic bacterial envelopes while simultaneously exerting intrinsic bactericidal activity, offering a dual function unattainable with vancomycin or PBA. Conjugates of representative AMPs such as polymyxin B and (KLAKLAK)₂ with porphyrin [75, 76], chlorin e6 [77], and phthalocyanine [78] scaffolds have demonstrated markedly enhanced bacterial accumulation and photodynamic eradication relative to the parent photosensitizers. These strategies are in principle transferable to BODIPY through amide or click coupling at the meso‐, 3‐, or 5‐positions, yet antibacterial BODIPY–AMP conjugates remain scarcely reported, with proteolytic degradation and hemolytic risk constituting the main translational barriers.

Nucleic acid aptamers, generated through systematic evolution of ligands by exponential enrichment (SELEX), recognize bacterial surface determinants with affinity and species‐level selectivity unattainable with small‐molecule ligands. Recent studies have validated this strategy on alternative photosensitizer platforms, including a mod‐SELEX‐derived aptamer carrying thirteen ruthenium polypyridyl complexes that bound Streptococcus pneumoniae with a K_d of 125 nM [79], and an MRSA‐specific aptamer‐functionalized upconversion nanoplatform loaded with Rose Bengal that achieved over 99.9% bactericidal efficiency [80]. BODIPY–aptamer antibacterial systems, however, have not yet been systematically developed, with nuclease degradation and SELEX cost remaining the principal practical barriers.

In summary, active targeting enabled by specific recognition ligand modification effectively overcomes the limitations of passive diffusion. As exemplified by vancomycin‐mediated recognition of Gram‐positive bacteria and glycan ligand‐assisted interfacial enrichment, the synergy between ligand targeting and complementary strategies, including charge regulation and microenvironment‐triggered responses, not only markedly improves photosensitizer accumulation and penetration within bacteria and biofilms, but also mitigates off‐target phototoxicity arising from nonspecific adhesion, thereby offering a more selective phototherapeutic modality for deep‐seated infections and mature biofilms. Macromolecular recognition motifs, such as antimicrobial peptides and aptamers offer broader spectra and species‐level selectivity, respectively, but remain underdeveloped on the BODIPY platform. Building on these advances, future efforts could further diversify ligand repertoires and optimize interfacial binding and penetration through multivalent presentation and multi‐target cooperativity, ultimately accelerating the clinical translation of targeted antibacterial photosensitizer systems.

3.2.3. Nitric Oxide (NO) Releasing Systems

Although PDT can achieve rapid and potent oxidative damage to bacteria through ROS, the short lifetime (nanosecond to microsecond scale) and limited diffusion radius (<20 nm) of ROS restrict its clearance efficiency in dense biofilms or deep‐seated infection foci [81, 82]. In contrast, nitric oxide (NO), as an endogenous gaseous signaling molecule, possesses a diffusion coefficient far exceeding that of macromolecular antibiotics, enabling effective penetration through the biofilm matrix to reach deep infection sites [83]. NO and the reactive nitrogen species (RNS) generated from its reactions can induce nitrosative stress, leading to the inactivation of key enzymes, damage to iron‐sulfur clusters, and genetic material damage through DNA base deamination and strand breakage [84, 85]. Furthermore, at low concentrations, NO can function as a signaling molecule to modulate bacterial quorum sensing, inducing loosening of the biofilm architecture and bacterial dispersal, thereby attenuating adhesion capacity and drug resistance [86]. Consequently, coupling the controlled release of NO with BODIPY‐based photosensitizing systems to construct a “light‐triggered, gas‐sensitized” combinatorial strategy has emerged as a frontier approach for overcoming biofilm‐associated drug resistance.

The study by Bao et al. revealed the critical role of aggregation‐state engineering in regulating the allocation between NO output and photothermal effects [39]. As discussed previously, by modulating the loading content of BDP14 within PEG‐b‐PCL micelles, a transition from the monomeric state to the J‐aggregated state can be achieved. This study demonstrated that such aggregation‐state transitions not only influence photothermal performance, but also directly determine NO release efficiency. Under low loading conditions (NP‐2, 1.4 wt%), monomeric molecules undergo efficient photolysis of N‐nitrosamine moieties upon white light irradiation, releasing approximately 10.6 µM of NO (yield ∼25%). However, as the loading content increased to 8.5 wt% (NP‐5), the tight molecular packing within J‐aggregates restricted the conformational changes required for photolysis of the N‐nitrosamine moieties, reducing the NO release yield to 1.3% while significantly elevating PCE. An intermediate loading content of 4.0 wt% (NP‐4) represented the optimal choice, balancing moderate NO release (∼13%) with favorable PCE (Figure 18a). Given the negligible responsiveness of N‐nitrosamine moieties to 808 nm laser irradiation, a sequential dual‐light‐source strategy was adopted, in which white light was first applied to trigger NO release, followed by 808 nm laser irradiation to activate PTT. In vitro antibacterial assays demonstrated that under sequential dual‐light‐source irradiation, NP‐4 achieved nearly 100% killing rates against E. coli, S. aureus, and MRSA, significantly outperforming the single‐light‐source treatment groups and exhibiting a pronounced synergistic antibacterial effect (Figure 18b).

FIGURE 18.

(a) Cumulative NO release of NP‐2, NP‐4, and NP‐5 micelles under WL irradiation determined by Griess assay. (b) Survival rate analysis of E. coli, S. aureus, and MRSA treated with NP‐4 micelles at different concentrations under white light, 808 nm laser, and sequential dual‐light irradiation. Reproduced with permission [39]. Copyright 2022, Wiley‐VCH. (c) Schematic diagram of the synthetic route of cationic covalent−organic‐framework‐encapsulated sodium nitroprusside (BG‐SNP) for combined antibacterial agents. Reproduced with permission [60]. Copyright 2023, American Chemical Society.

In addition to achieving photoresponsive NO release through molecular structural design, another representative strategy involves the construction of multicomponent synergistic platforms via electrostatic interactions. Wang et al. developed a BODIPY‐based cationic porous organic polymer (BDP35) and encapsulated the negatively charged sodium nitroprusside (SNP) into the positively charged skeleton through in situ ion exchange, yielding the nanocomposite BG‐SNP [60]. This system integrates four synergistic mechanisms within a single platform: cationic enrichment, PDT, PTT, and NO gas therapy (Figure 18c). BDP35 exhibited a significantly positive zeta potential, facilitating binding to negatively charged bacterial membranes through electrostatic interactions; under 638 nm laser irradiation, PCE was approximately 21.4%. PTT not only directly damages bacterial membranes, but also significantly accelerates the rate of NO release from SNP and enhances ROS penetration. In vitro experiments confirmed that BG‐SNP achieved bactericidal efficiencies exceeding 99% against both S. aureus and E. coli after 638 nm laser irradiation for 10 min. In vivo studies further demonstrated that BG‐SNP could elicit immune responses and exploit low‐concentration NO to promote collagen deposition and neovascularization, significantly accelerating the healing of infected wounds.

Overall, BODIPY‐based light‐triggered NO delivery strategies achieve in situ, on‐demand release of NO through the coupling of “optical signal‐gaseous effector,” thereby overcoming the bottlenecks associated with the difficulty of storing gaseous molecules and controlling their dosage. More importantly, the diffusion and penetration capabilities of NO/RNS far exceed those of macromolecular drugs, effectively addressing the limitation of restricted “effective action distance” encountered by conventional phototherapy in dense biofilm interiors. Meanwhile, the multifaceted biological effects of NO in antibacterial activity, immune regulation, and tissue repair provide a unique and translationally promising design strategy for constructing integrated platforms that combine infection eradication with tissue regeneration.

3.3. Self‐Assembled BODIPY Nanostructures

Although molecular‐level functionalization has significantly expanded the spectral tunability and functional diversity of BODIPY, most hydrophobic BODIPY derivatives inevitably undergo nonspecific aggregation in physiological aqueous media and complex in vivo environments. This leads to nanoparticle precipitation, particle size distribution drift, diminished colloidal stability, and ACQ, ultimately compromising their effective dispersibility under physiological conditions, retention at infection sites, and antibacterial efficacy at bacterial cell membrane and biofilm interfaces [43, 87]. To address this challenge, non‐covalent‐driven self‐assembly or co‐assembly strategies based on amphiphilic molecules offer new design paradigms. Driven synergistically by multiple noncovalent interactions, including hydrophobic effects, π‐π stacking, and electrostatic and/or hydrogen‐bonding interactions, BODIPY derivatives can either directly assemble into nanostructures such as micelles or vesicles [27, 61], or coassemble with amphiphilic polymers to form more structurally controllable core‐shell nanocomposite systems [46]. Such nano‐assemblies not only substantially enhance the aqueous solubility and in vivo stability of BODIPY, but more importantly, the assembly microenvironment enables systematic modulation of photophysical properties and excited‐state energy dissipation pathways.

Conventional nano‐delivery systems typically rely on large quantities of inert carriers (such as polymeric matrices or liposomes), resulting in drug loading efficiencies (DLE) generally below 10%, which limits therapeutic efficacy. To overcome this bottleneck, carrier‐free self‐assembly strategies have emerged. Shi et al. developed unadulterated BODIPY nanoparticles that require no surfactants or auxiliary agents [27]. The BODIPY derivatives they designed possess specific amphiphilic structures that enable self‐assembly into stable nanoparticles in water through intermolecular hydrophobic interactions. Since the entire nanoparticle is composed exclusively of self‐assembled BODIPY molecules, the theoretical drug loading approaches 100%, not only avoiding the potential toxicity or metabolic burden associated with carrier materials, but also exhibiting excellent antibacterial activity against S. aureus and wound healing‐promoting capability under light irradiation (Figure 19a). However, conventional BODIPY molecules in the aggregated state typically exhibit ACQ effects, which severely limits their application in PDT. To address this issue, Liu et al. proposed an “assembly‐enhanced” strategy [61]. They synthesized a series of amphiphilic BODIPY derivatives bearing pyridinium groups and discovered that the nanoparticles formed by self‐assembly of these molecules in the aqueous phase exhibited ¹O₂ generation efficiencies significantly higher than those of the corresponding monomeric species in organic solvents (Figure 19b). This counterintuitive enhancement was attributed to the supramolecular self‐assembly process, which reduces the energy gap between the excited singlet and triplet states, thereby strengthening ISC and effectively suppressing non‐radiative decay of excited‐state energy. This study demonstrates that, through rational molecular engineering and controlled self‐assembly, “aggregation,” which is typically regarded as a detrimental factor, can be converted into a key advantage for enhancing antibacterial photodynamic efficacy.

FIGURE 19.

(a) Synthesis and antibacterial application of BNP2 in vivo. Reproduced with permission [27]. Copyright 2023, Elsevier. (b) Schematic illustration of assembly‐enhanced ¹O₂ generation of BODIPY molecules. Reproduced with permission [61]. Copyright 2023, Royal Society of Chemistry. (c) Schematic representation of the preparation and application of the BDP37 NPs for PTT/PDT synergic therapy of MRSA‐infected mice. Reproduced with permission [46]. Copyright 2022, Springer.

Co‐assembly of hydrophobic BODIPY molecules with amphiphilic polymers represents a well‐established and versatile nanoformulation strategy. This self‐assembly process not only endows photosensitizers with excellent aqueous dispersibility and biocompatibility, but the resulting hydrophobic core‐hydrophilic shell architecture also effectively shields the photosensitizer from interference by the complex physiological environment. To further extend the application of BODIPY to deep‐seated infections, Song et al. employed cholesterol‐modified polyethylene glycol (Chol‐PEG₂₀₀₀‐NH₂) as an amphiphilic carrier to construct NIR‐responsive aza‐BODIPY co‐assembled nanoparticles (BDP37 NPs) (Figure 19c) [46]. Benefiting from the planar rigid structure of the aza‐BODIPY scaffold and the strong absorption induced by intermolecular J‐aggregation, these nanoparticles exhibited excellent PCE and ROS generation capability under 808 nm laser irradiation. Triggered by a single 808 nm wavelength laser, the BDP37 NPs efficiently eradicated S. aureus and E. coli through synergistic PTT and PDT mechanisms. In a murine MRSA‐infected wound model, the nanoparticles significantly accelerated collagen deposition and epidermal reconstruction, achieving nearly complete wound healing by Day 14. The 808 nm laser offers deeper tissue penetration and lower biological tissue absorption, rendering the BDP37 NPs more suitable for treating deep soft tissue and bone infections. This work demonstrates that through molecular structure optimization combined with rational assembly strategies, the application of BODIPY photosensitizers can be extended from superficial infections to the realm of deep tissue antibacterial therapy.

In summary, self‐assembly strategies, through precise modulation of the aggregation state and microenvironment of BODIPY, not only effectively address the challenges of dispersibility and stability that conventional hydrophobic photosensitizers face under physiological conditions, but also achieve a paradigm shift from “ACQ” to “aggregation‐enhanced” photosensitization. This transformation provides a viable strategy for developing highly efficient, low‐toxicity antibacterial photodynamic nanoplatforms. Nevertheless, how to further enhance the penetration depth of nano‐assemblies in deep‐seated infected tissues, overcome complex biofilm barriers, and achieve greater targeting precision remain critical challenges that urgently need to be addressed in this field.

4. Framework and Polymer‐Based BODIPY Platforms

Although non‐covalent self‐assembly significantly improves the dispersibility of hydrophobic BODIPY dyes in aqueous media, in complex infection environments, such supramolecular assemblies are susceptible to multiple destabilizing factors including ionic strength fluctuations, protein corona formation, and dynamic dilution effects. These perturbations can lead to structural dissociation, premature photosensitizer leakage, and diminished colloidal stability, ultimately compromising local retention efficiency and therapeutic reliability. In contrast, covalent anchoring of BODIPY onto macromolecular scaffolds or polymeric platforms offers a superior strategy for constructing antibacterial photosensitive materials that simultaneously possess structural robustness and functional versatility. On one hand, crystalline COFs, by virtue of their ordered crystalline architectures and functionalizable pore channels, regulate the spatial arrangement of chromophores through pore confinement and site isolation mechanisms. This not only effectively suppresses ACQ, but also enables the integration of PDT and PTT in a combined therapeutic modality [28, 88, 89]. On the other hand, functional polymeric materials such as antibacterial coatings, photoactive films, and hydrogel dressings can achieve efficient photosensitizer loading through crosslinking or chemical grafting approaches [90, 91]. These polymeric platforms, while maintaining favorable biocompatibility and preventing payload leakage, provide versatile material platforms for a wide range of clinical application scenarios, including antimicrobial treatment of medical device surfaces, infected wound management, and environmental disinfection.

4.1. BODIPY‐Based Covalent Organic Frameworks (COFs)

COFs are a class of two‐ or three‐dimensional porous organic networks constructed from light elements (C, H, O, N, B, etc.) linked through covalent bonds, typically exhibiting a degree of crystallinity, with their topological structures and pore characteristics being tunable and functionalizable during the molecular assembly process [92, 93]. In the field of antibacterial phototherapy, covalent anchoring of BODIPY units within COF backbones enables effective suppression of π‐π stacking aggregation of chromophores through site isolation and pore confinement mechanisms. Moreover, the tunable intrapore microenvironment and mass transport channels enhance oxygen molecule diffusion and interfacial accessibility to infection foci, thereby providing a foundation for the coordinated integration of ROS generation and PTT [94]. Building upon these advantages, recent research directions in BODIPY‐COF antibacterial platforms can be categorized into two main themes: first, backbone functionalization and heterogeneous unit integration or incorporation of metallic/carbon‐based components to achieve multi‐mechanistic coupling and synergistic amplification; second, pore/side‐chain modification for charge reconstruction to enhance bacterial interfacial adhesion and capture, thereby improving inactivation efficiency in complex infection models.

At the backbone design level, covalent integration of photosensitizers such as porphyrins and BODIPY into a single COF framework can synergistically enhance light absorption, promote the cooperative interplay between ROS generation and photothermal effects, and strengthen interactions at the bacterial interface, thereby improving overall antibacterial efficiency. Zhao et al. proposed an “all‐in‐one” strategy, constructing a heterogeneous backbone COF (BDP38) through Schiff‐base condensation of tetraphenylporphyrin (Tph) and BODIPY (Figure 20a) [28]. In this system, porphyrin serves as the electron donor and BODIPY as the electron acceptor, establishing efficient ICT between the two units. Femtosecond transient absorption spectroscopy directly captured a charge‐separated state (Tph•⁺‐BDP•⁻) with a significantly prolonged lifetime of 1084.3 ps, substantially surpassing that of the single‐component porphyrin‐based COF‐366 (370.8 ps), confirming that donor‐acceptor coupling can effectively stabilize charge separation within the framework (Figure 20b). This long‐lived charge‐separated state, on one hand, facilitates the ISC process to enhance ROS generation, and on the other hand, intensifies non‐radiative thermal dissipation. Ultimately, under the “all‐in‐one” synergistic mechanism, BDP38 achieved a 97% inhibition rate against E. coli, significantly outperforming the 54% achieved by COF‐366 (Figure 20c).

FIGURE 20.

(a) Schematic synthesis of BDP38 and illustration of ROS generation and photothermal conversion under light irradiation. (b) Femtosecond transient absorption spectra of BDP38 (left) and time profiles at 715 nm of BDP38 and COF‐366 (right). (c) Inhibition ratios of E. coli corresponding to different treatments under dark and light conditions. Reproduced with permission [28]. Copyright 2023, Elsevier.

Building on the integration of photosensitizers within COF frameworks, the further introduction of metal‐ or carbon‐based components enables phototherapy and contact‐active antibacterial action to be combined within a single platform. Liu et al. constructed a sulfur‐containing porous COF from BDP39 and sulfur‐doped carbon quantum dots (CD‐S‐3), and exploited the affinity between pore‐confined sulfur sites and Ag to realize the in situ growth of silver nanoparticles (AgNPs), affording COF_{BDP/CD‐S‐3}‐Ag (Figure 21a). Compared with the Ag‐free COF_{BDP/CD‐S‐3}, this composite exhibited wavelength‐dependent multimodal therapeutic behavior: upon 420 nm excitation it efficiently generated ¹O₂, whereas under 808 nm laser irradiation it predominantly delivered robust photothermal heating with good cycling stability [88]. Under stepwise dual‐light irradiation (808 nm + 420 nm), COF_{BDP/CD‐S‐3}‐Ag synergistically combined AgNPs‐bacterial envelope interactions and Ag⁺ release with light‐activated PDT and PTT, thereby markedly reducing MICs against E. coli, S. aureus, MRSA, and Monilia albicans, and providing a new design route toward broad‐spectrum, highly efficient hybrid antibacterial platforms.

FIGURE 21.

(a) The schematic representation for preparing COF_{BDP/CD‐S‐3}‐Ag. Reproduced with permission [88]. Copyright 2023, Elsevier. (b) Schematic diagram of photothermal and photodynamic antibacterial and wound healing based on cationic BDP40. Reproduced with permission [89]. Copyright 2024, American Chemical Society.

To further strengthen the interactions between COFs and bacterial surfaces, chemical functionalization of the COF pore walls or pendant side chains represents another effective strategy. Ma et al. developed a post‐methylation approach to convert a neutral BODIPY‐COF (PB‐COF) into a cationic ionic COF (BDP40) (Figure 21b) [89]. PB‐COF was synthesized via a condensation reaction between a dialdehyde‐functionalized BODIPY and piperazine, followed by iodomethane‐mediated methylation to generate quaternary ammonium cations on the piperazine units, thereby switching the surface potential from −24.1 mV to +27.5 mV. This charge reversal markedly enhanced bacterial adsorption through electrostatic interactions. More importantly, methylation simultaneously improved both the photothermal and photodynamic activities of the material. This simple post‐functionalization strategy, which simultaneously reinforces multiple antibacterial mechanisms, offers a new avenue for developing highly efficient, broad‐spectrum, and reusable photoresponsive antibacterial materials.

In summary, COFs, owing to their tunable pore architectures and readily functionalizable backbones, can effectively mitigate ACQ of hydrophobic BODIPY dyes under physiological conditions. Through either “all‐in‐one” framework construction or post‐synthetic modification, BODIPY‐COF platforms enable multimodal synergistic antibacterial therapy that integrates PDT, PTT, and contact‐killing effects. These studies not only elucidate the structure‐activity relationships of BODIPY‐COF systems, but also demonstrate the promise of crystalline porous organic frameworks for efficient antibacterial phototherapy.

4.2. BODIPY‐Based Functional Polymers

The choice of polymer matrix must be tailored to the target clinical scenario, as different scaffolds differ substantially in biocompatibility, degradation profile, drug‐loading mode, and processability. Natural polysaccharides (e.g., chitosan) and proteins (e.g., gelatin) are particularly suited to wound dressings, owing to their inherent biocompatibility, hemostatic activity, mild gelation conditions, and abundant functional groups for covalent BODIPY anchoring; however, their relatively low mechanical stability limits their use in load‐bearing implants. Synthetic polymers offer complementary advantages. Polyurethane (PU) substrates provide elastic and durable platforms with long‐term structural integrity, onto which BODIPY‐functionalized bioactive layers can be grafted, making them well matched to hernia meshes, catheters, and other implantable devices [91]. Poly(lactic‐co‐glycolic) acid (PLGA), an FDA‐approved aliphatic polyester, enables tunable hydrolytic degradation over weeks to months and high photosensitizer loading capacity, and has been widely explored for resorbable scaffolds and depot‐type photodynamic delivery systems [95, 96]. Building on these complementary properties, the following discussion focuses on representative chitosan‐based wound dressings and PU‐based implant coatings to illustrate how rational chemical design can overcome the intrinsic hydrophobicity and ACQ of BODIPY across distinct clinical contexts.

In studies of BODIPY‐based photosensitizing systems, non‐crystalline functional polymers have emerged as a major research focus in recent years, owing to their excellent morphological tunability and processability [97]. Compared with conventional crystalline COF materials, functional polymers typically exhibit low crystallinity or amorphous characteristics, endowing them with clear advantages in the fabrication of flexible materials and in their potential for clinical translation [98]. Specifically, functional polymers can be processed into hydrogels, coatings, or flexible films, thereby accommodating a wide range of application scenarios with complex geometries [99, 100]. In addition, polymer matrices offer abundant sites for chemical modification; through side‐chain engineering or post‐functionalization, cationic groups, gas donors, or bioactive components (e.g., hyaluronic acid and gelatin) can be incorporated to enable multimodal synergistic therapy [91]. This section will discuss BODIPY‐based antibacterial materials constructed on non‐crystalline functional polymer scaffolds. Based on their physical forms and intended application contexts, we will focus on antibacterial hydrogel coatings and bioactive films, highlighting how rational chemical design can overcome the inherent hydrophobicity and ACQ of BODIPY molecules to achieve efficient, safe, and broad‐spectrum antibacterial performance.

Chitosan (CS), a naturally occurring cationic polysaccharide with good biocompatibility, biodegradability, and intrinsic antibacterial activity, provides a readily functionalizable polymeric scaffold for constructing photosensitive materials. Zhao et al. developed a covalently conjugated chitosan‐BODIPY polymeric photosensitizing system. Briefly, they first synthesized an alkynyl‐terminated BODIPY small molecule (BOD‐4) and then anchored BOD‐4 onto the chitosan backbone via coupling between the alkyne group and the amino groups of chitosan to afford CS‐I; subsequently, pyridine moieties were introduced to yield CS‐Py, and final quaternization of the pyridine nitrogen furnished the cationic photosensitizers BDP41 (Figure 22a) [90]. Incorporation of the cationic quaternary ammonium and pyridyl motifs not only markedly improved aqueous solubility, thereby overcoming the intrinsic hydrophobicity of BODIPY, but also strengthened electrostatic interactions with negatively charged bacterial membranes, promoting photosensitizer accumulation on bacterial surfaces. Under white‐light irradiation, BDP41 efficiently generated ¹O₂. Notably, compared with the small‐molecule BOD‐Me, BDP41 exhibited a stronger ROS‐generating capability, which was attributed to the spatial isolation of BODIPY units by the chitosan scaffold, effectively suppressing ACQ. Taking advantage of the excellent film‐forming property of chitosan, BDP41 were further processed into films and coated onto transparent band‐aids. Agar diffusion assays demonstrated that, after white‐light exposure, this photoactive dressing produced pronounced antibacterial effects against E. coli and S. aureus, supporting its practical utility as a topical antimicrobial dressing. This design integrates the wound‐healing‐promoting properties of chitosan with photodynamic bactericidal activity, providing a new strategy for the treatment of wounds infected with multidrug‐resistant bacteria.

FIGURE 22.

(a) Structures of BDP41. Reproduced with permission [90]. Copyright 2025, Elsevier. (b) Schematic illustration of the properties and acting mechanisms of PU‐GHB. Reproduced with permission [91]. Copyright 2023, Wiley.

Implant‐associated infections are often initiated by bacterial adhesion to device surfaces and subsequent biofilm formation; when compounded by MDR and the resulting failure of antibiotic therapy, postoperative infection control becomes particularly challenging. Zhang et al. developed a multifunctional antibacterial coating based on a heavy‐atom‐free BODIPY photosensitizer (BDP42), enabling synergistic bacterial eradication via combined PTT and PDT. In terms of material design, BDP42 bears reactive aldehyde groups and was crosslinked with amino‐rich gelatin and multi‐aldehyde oxidized hyaluronic acid (OHA) through Schiff‐base reactions, forming a uniform coating with a thickness of ∼60 µm on the surface of a polyurethane hernia mesh (PU‐GHB) (Figure 22b) [91]. The high hydrophilicity of OHA effectively suppressed bacterial adhesion and reduced the risk of tissue adhesion. Under 808 nm laser irradiation, BDP42 exhibited a favorable PCE together with a high singlet oxygen quantum yield. Compared with either monotherapy, the combined PTT/PDT modality increased the bactericidal efficacy against MRSA to 99.99%, and comparable activity was also achieved against S. aureus, E. coli, and vancomycin‐resistant Enterococcus (VRE). Mechanistic studies indicated that photothermal heating perturbs the phospholipid bilayer, decreasing bacterial activity and increasing membrane permeability, thereby facilitating intracellular diffusion of ROS and ultimately amplifying membrane disruption and protein leakage. In addition, by leveraging the characteristic absorption of BDP42 at 725 nm, the coating endowed the device with photoacoustic imaging capability, allowing real‐time monitoring of the implant's location and structural integrity in vivo. This study provides an innovative strategy for developing medical‐device coatings that integrate anti‐infective, anti‐adhesion, and imaging functionalities within a single platform.

In summary, BODIPY‐based photosensitizing systems built on functional polymer scaffolds, enabled by diversified material‐format engineering, have expanded their applicability from superficial wound care to infection prevention for implantable medical devices. These design strategies not only overcome the intrinsic hydrophobicity and ACQ of BODIPY, but also systematically address the practical limitations of small‐molecule photosensitizers in terms of solubility, stability, and processability.

5. Organic‐Inorganic Hybrid BODIPY Nanoplatforms

Although the aforementioned molecular engineering and organic nanoassembly strategies have improved the aqueous dispersibility, colloidal stability, and antibacterial performance of BODIPY‐based photosensitizing systems to a certain extent, platforms relying solely on organic components still suffer from several limitations. First, PCE and photothermal stability remain restricted, making it difficult to achieve sustained and efficient PTT under low‐power‐density laser irradiation [101]. Second, these systems lack long‐acting antibacterial mechanisms; upon cessation of light irradiation, ROS are rapidly quenched, rendering the system unable to continuously eradicate residual bacterial strains or to prevent bacterial re‐adhesion and biofilm regeneration. Third, when confronted with the dense EPS barrier of mature biofilms, the penetration depth and physical disruption capacity of purely organic nanomicelles are often inadequate [102, 103]. To address these challenges, hybridizing BODIPY with inorganic nanomaterials that possess intrinsic photothermal conversion, catalytic activity, or metal ion release capabilities, such as two‐dimensional MXenes, metal oxides, and MOFs/zeolitic imidazolate frameworks (ZIFs), has emerged as a key strategy for constructing high‐performance multimodal synergistic antibacterial platforms [104, 105, 106]. In this section, organic‐inorganic hybrid BODIPY nanoplatforms are classified into two categories for discussion: non‐porous inorganic carrier platforms represented by MXenes and metal oxides, and porous or coordination‐driven platforms represented by metal‐organic frameworks (MOFs/ZIFs) and metal‐coordination assemblies.

5.1. MXene and Metal Oxide Hybrid Platforms

MXenes, by virtue of the high specific surface area conferred by their layered structure, tunable surface functional groups, and broadband light absorption properties, have emerged as representative inorganic carriers for constructing BODIPY‐based synergistic PDT/PTT antibacterial platforms. MXenes exhibit favorable hydrophilicity and functionalizability, while their excellent NIR light absorption characteristics render them ideal photothermal conversion materials. However, MXenes themselves lack the capacity for ROS generation and are susceptible to oxidative degradation in aqueous solution. Consequently, hybridization with organic photosensitizers has become a key strategy for enhancing their antibacterial versatility and stability [107].

Taking the classical Ti₃C₂T_X as an example, Lv et al. designed and synthesized a pyridine‐functionalized BODIPY derivative (PBP), which was protonated under acidic conditions to form positively charged PBP‐HCl and subsequently assembled onto the negatively charged Ti₃C₂T_X nanosheet surface via electrostatic interactions, yielding the PBP‐MXene composite (Figure 23a) [104]. XRD analysis revealed that the interlayer spacing of MXene increased significantly from approximately 1.18 nm to 2.16 nm upon PBP intercalation, confirming the successful incorporation of PBP into the MXene interlayers. This expansion of the interlayer distance is favorable for increasing the active surface area and exposing additional photothermal conversion sites. The resulting hybrid system exhibited a pronounced photothermal effect under 808 nm NIR irradiation, while PBP demonstrated excellent ROS generation capability upon visible light excitation. PBP‐MXene achieved bactericidal rates of 99.8% against E. coli and 99.7% against S. aureus, significantly outperforming pristine MXene at the same concentration. Mechanistic investigations revealed that thermal ablation induced by the photothermal effect disrupted bacterial cell walls and membrane proteins, while ROS‐mediated oxidative stress provided a synergistic enhancement, collectively realizing an amplified antibacterial efficacy through the cooperative action of PTT and PDT.

FIGURE 23.

(a) Schematic illustration of the preparation process of PBP‐MXene. Reproduced with permission [104]. Copyright 2025, Elsevier. (b) Schematic illustration of BDP43‐ZnO synthesis. Reproduced with permission [106]. Copyright 2024, Elsevier. (c) Schematic preparation route of BODIPY‐Mo₂C nanosheets. Reproduced with permission [105]. Copyright 2024, Elsevier.

Compared to the extensively studied Ti₃C₂T_X, Mo₂C‐type MXenes have also attracted considerable attention owing to their distinctive electronic structure and superior environmental stability. Lv et al. reported the construction of a BODIPY‐Mo₂C nanoantibacterial agent through an electrostatic self‐assembly strategy, in which protonated BODIPY‐NH₃ ⁺ was employed to modify Mo₂C nanosheets (Figure 23c) [105]. The study revealed that Mo₂C exhibited a high PCE of up to 42.6% under 808 nm laser irradiation. The incorporation of BODIPY endowed the composite with a characteristic absorption peak at 500 nm and the capacity for ¹O₂ generation. Antibacterial assays demonstrated that both Mo₂C and BODIPY‐Mo₂C achieved nearly 100% bactericidal rates under NIR irradiation at high concentrations; however, at lower concentration gradients, BODIPY‐Mo₂C displayed significantly superior antibacterial activity compared to pristine Mo₂C. These results demonstrate that the introduction of BODIPY‐induced photodynamic oxidative damage can effectively compensate for the limitations of PTT alone at reduced dosages, thereby enhancing the overall therapeutic efficacy.

In addition to two‐dimensional MXene materials, metal oxides such as ZnO can also form synergistically enhanced systems with BODIPY photosensitizers. ZnO has attracted considerable attention owing to its photocatalytic ROS generation capability and the chemical bactericidal action of released Zn²⁺; however, its wide bandgap restricts its photoresponse to the ultraviolet region, greatly limiting practical applications under visible light irradiation. Lin et al. designed an imidazole‐bearing BODIPY photosensitizer (BDP43) and exploited the Zn‐N coordination interaction between the imidazole nitrogen atoms and the surface zinc atoms of ZnO to successfully prepare the BDP43‐ZnO composite via self‐assembly (Figure 23b) [106]. Compared with pristine ZnO, the introduction of BDP43 significantly broadened the visible light absorption of the material and reduced the bandgap energy. Mechanistic studies revealed that under LED irradiation, BDP43‐ZnO generated multiple ROS species (•OH, •O₂ ⁻, ¹O₂), wherein BDP43 primarily contributed to ¹O₂ production, while the valence band holes of ZnO oxidized H₂O to generate •OH and the conduction band electrons reduced O₂ to produce •O₂ ⁻. Notably, the ESR signals of all three ROS species were significantly stronger for BDP43‐ZnO than for ZnO alone, demonstrating that the synergism between BDP43 and ZnO effectively enhanced the overall ROS yield. Under illumination, Zn²⁺ release from BDP43‐ZnO was also markedly higher than that from pristine ZnO, indicating that the incorporation of BDP43 promoted light‐induced ion dissolution. It is noteworthy that the effective concentration required by this system was considerably lower than those of MXene‐based platforms, which can be attributed to the multi‐mechanistic synergy of enhanced visible light absorption, augmented ROS generation, and accelerated Zn²⁺ release.

In summary, MXenes and metal oxide hybrid platforms, by integrating the photodynamic therapeutic function of BODIPY with the intrinsic photothermal conversion and ion release properties of inorganic components, not only effectively mitigate ACQ and poor water solubility issues of BODIPY, but also significantly broaden the scope of antibacterial therapeutic applications. Two‐dimensional MXenes (such as Ti₃C₂T_X and Mo₂C), leveraging their high specific surface area and excellent NIR absorption properties, achieve dual‐wavelength‐excited PDT/PTT synergy upon electrostatic assembly with BODIPY. Metal oxides (such as ZnO), through coordination bond‐driven assembly with BODIPY, enable bandgap modulation and visible light‐activated multi‐mechanistic synergistic bactericidal activity.

5.2. MOF/ZIF and Metal‐Coordination‐Driven BODIPY Hybrid Platforms

MOFs, ZIFs, and metal coordination‐driven nanoassemblies, by virtue of their versatile metal‐ligand chemistry, tunable pore architectures, and the inherent biological activity of metal ions, offer another important class of inorganic hybridization strategies for constructing BODIPY‐based multifunctional antibacterial platforms. The defining feature of these platforms lies in the formation of metal‐organic coordination bonds, which can either construct highly ordered porous frameworks (such as ZIF‐8) or directly drive the nanoscale assembly of BODIPY molecules through simple coordination interactions. Although the two strategies differ in their degree of structural ordering, both exploit the coordination chemistry of metal ions to achieve stable loading of BODIPY, suppression of ACQ, and controlled release of metal ions, thereby integrating PDT with chemical bactericidal action.

In terms of the porous framework strategy, Shen et al. employed carboxyl‐modified BODIPY (BDP44) as a functional ligand, which was combined with Zn(NO₃)₂ and 2‐methylimidazole via room‐temperature coordination‐driven self‐assembly to successfully construct a BODIPY‐functionalized ZIF‐8 nanocomposite (BDP44) (Figure 24a) [29]. In this system, BDP44 forms Zn‐O coordination bonds through its carboxyl group with Zn²⁺, serving not only as a photosensitizer, but also as a structure‐directing agent that induces a morphological transformation from the typical rhombic dodecahedral geometry of ZIF‐8 to a hollow spherical microporous structure. This three‐dimensional porous architecture effectively suppresses intermolecular π‐π stacking of BODIPY molecules through spatial isolation. The incorporation of BODIPY imparted multiple synergistic effects: broadening the photoresponse range from the ultraviolet to the visible region while reducing the bandgap energy, and effectively suppressing the recombination of photogenerated electron‐hole pairs to facilitate ROS generation. Under LED irradiation, the material achieved highly efficient bactericidal activity through the synergistic action of ROS production and Zn²⁺ release, exhibiting excellent inhibitory effects against both E. coli and S. aureus that were significantly superior to those of ZIF‐8 or BODIPY alone.

FIGURE 24.

(a) Schematic illustration of BODIPY‐ZIF‐8 synthesis. Reproduced with permission [29]. Copyright 2022, Elsevier. (b) Preparation of BCu NPs for antibacterial application. Reproduced with permission [108]. Copyright 2022, American Chemical Society.

Beyond achieving stable loading of BODIPY and light‐induced metal ion release through porous MOF frameworks, the direct in situ construction of nanoassemblies via metal‐ligand coordination interactions represents another facile and efficient strategy. Unlike the ordered framework of ZIF‐8, these systems do not form crystalline porous scaffolds; instead, they assemble hydrophobic BODIPY molecules into water‐dispersible nanoparticles through the bridging coordination action of metal ions. Wang et al. exploited the coordination interactions among BDP45, CuSO₄, and L‐phenylalanine to prepare BCu NPs in a one‐step aqueous‐phase process (Figure 24b) [108]. This system integrates multiple antibacterial mechanisms: the intrinsic bactericidal activity of Cu²⁺, ¹O₂‐mediated oxidative damage generated by BDP45 under green light irradiation, and the intimate contact between nanoparticles and bacterial membranes that facilitates the efficient accumulation of both ROS and Cu²⁺ at the bacterial surface.

In summary, BODIPY hybrid platforms based on MOF/ZIF frameworks and metal coordination assemblies demonstrate remarkable advantages in multi‐mechanistic synergistic antibacterial action. In the BODIPY‐ZIF‐8 system, the three‐dimensional ordered porous framework suppresses ACQ through spatial confinement effects, while the controllable degradation of the framework enables light‐induced sustained release of Zn²⁺, thereby integrating PDT with chemical bactericidal action to achieve broad‐spectrum, high‐efficiency sterilization at ultralow concentrations. In metal coordination assemblies, the intimate contact between nanoparticles and bacterial membranes facilitates the efficient accumulation of both ROS and Cu²⁺ at the bacterial surface. These strategies not only overcome the performance bottlenecks of single organic photosensitizers, but also, through the introduction of metal ions, enable sustained chemical bactericidal activity after cessation of light irradiation, offering new design paradigms for addressing complex clinical challenges such as biofilm infections and drug‐resistant bacteria.

Across Sections 2, 3, 4, 5, the design of BODIPY‐based antibacterial phototherapy has evolved from molecular‐level excited‐state engineering to supramolecular assembly and organic–inorganic hybridization, with each class exhibiting distinct photophysical and antibacterial profiles. To facilitate direct cross‐comparison, Table 1 consolidates the absorption wavelengths, singlet oxygen quantum yields (Φ _Δ), photothermal conversion efficiencies (η_PT), irradiation conditions, therapeutic modalities, and antibacterial activities of representative systems discussed throughout this review. This consolidated overview lays the groundwork for the critical assessment of current limitations and future directions presented in Section 6.

TABLE 1.

Summary of representative BODIPY‐based photosensitizers and nano‐platforms for antibacterial phototherapy.

Compound	λabs (nm)	ROS generation / ηPT a	Light source b	Modality	Bacteria c	Antibacterial activity d	Ref.
BDP3	535	DPBF↓ 98.9% (160 s)	Green LED, 18 mW cm−2, 5 min	PDT	S. aureus	MIC = 10 nM; biofilm inhibition > 99%	[34]
BDP8	538	Φ Δ = 0.69	530 nm LED, 110 mW cm−2, 30 min	PDT	S. aureus	∼100% eradication at 20 µM	[35]
BDP11	640	ηPT = 33.1%	660 nm laser, 300 mW cm−2, 5 min	PDT + PTT	E. coli, S. aureus, C. albicans	MBC ≈ 10 µg mL−1	[36]
BDP12	517 / 708	DPBF↓ ∼78% (120 s); ηPT = 39.1%	730 nm laser, 1.0 W cm−2, 10 min	PDT + PTT	S. aureus	∼92% eradication at 100 µg mL−1	[37]
BICF NPs	∼680	DPBF↓ ∼42% (100 s); ηPT = 30.1%	685 nm laser, 0.6 W cm−2, 10 min	PDT + PTT	S. aureus, E. coli	MIC = 40 µg mL−1	[38]
BDP‐NO@PEG‐ b‐PCL	711 (M‐band), 820 (J‐band)	ηPT = 48.5%	White light, 63 mW cm−2, 12 min + 808 nm laser, 375 mW cm−2, 5 min	NO + PTT	S. aureus, E. coli, MRSA	∼100% eradication at 333 µg mL−1; in vivo MRSA wound superior to vancomycin	[39]
BDP15	523	Φ Δ = 0.59	527 nm LED, 69 mW cm−2, 25 J cm−2	PTT	S. aureus, E. coli	S. aureus: MIC = 4.17 µM, MBC = 6.25 µM; E. coli: MIC = MBC = 25 µM	[40]
BDP16‐TMA NPs	∼530	Φ Δ = 0.76	Green light, 12 mW cm−2, 10 min	PDT	S. aureus, E. coli	S. aureus: MIC = 20 ng mL−1; E. coli: ∼100% eradication at 25 µg mL−1	[24]
BDP17	650	Φ Δ = 0.52	650 nm laser, 10 J cm−2	PDT	S. aureus	MIC = 4 µg mL−1; biofilm inhibition = 95.37%	[25]
BDP19 NPs	533	DPBF↓ ∼90% (60 s)	Green light, 12 mW cm−2, 10 min	PDT	S. aureus	MIC = 0.3 µg mL−1; ∼70% biofilm formation inhibition at 6 µg·mL−1	[55]
BDP22	547	Φ Δ = 0.84	Halogen lamp, 90 mW cm−2, 15 min (81 J cm−2)	PDT	S. aureus	MIC = 0.63‐1.25 µM; >99.99% eradication at 2 µM	[56]
BDP27	550	DPBF↓ ∼75% (50 s)	Green light, 18 mW cm−2, 10 min	PDT	S. aureus, E. coli	S. aureus: MIC = 0.9 µM; E. coli: MIC = 2 µM	[52]
IBPAAS	630	DPBF↓ ∼60% (40 s, pH 5.5)	550 nm laser, 0.2 W cm−2	PDT	S. aureus, E. coli	Near‐complete eradication at pH 5.5 + light; ∼85% biofilm dispersal	[53]
BCNBA@ZIF	500–600	Φ Δ = 0.14	Blue LED, 4 W, 30 min	PDT + cascade release	E. coli	>99% eradication at 0.4 mg mL−1	[57]
BDPV	650–850	ηPT = 35.9%	808 nm laser, 0.3 W cm−2, 5–10 min	PDT + PTT	MRSA	MIC = 80 µg mL−1	[59]
BG‐SNP	638	DPBF↓ 91.2% (10 min); ηPT = 21.4%	638 nm laser, 1.0 W·cm−2, 10 min	PDT + PTT + NO	S. aureus, E. coli	>99% eradication at 250 µg mL−1	[60]
BNP2	543	ICG↓ 68% (160 s)	Green LED, 18 mW·cm−2, 5 min	PDT	S. aureus	>99% eradication at 10 ng·mL−1; biofilm inhibition >99%; in vivo wound healing 90.7%	[27]
nano‐PSs	∼660	Φ Δ = 0.56	660 nm light, 50 mW·cm−2, 10 min	PDT	MRSA	MIC = 1 µM; 99.86% killing at 2 µM with light	[61]
BDP37 NPs	639 / 776	DPBF↓ ∼63% (10 min)	808 nm laser, 2.0 W·cm−2, 10 min	PDT + PTT	S. aureus, E. coli, MRSA	>99.9% eradication at 68 µM	[46]
BDP38	500 / 715	ηPT = 29.9%	Visible light, 50 mW·cm−2, 30 min	PDT + PTT	E. coli	97% eradication	[28]
COFBDP/CD‐S‐3‐Ag	420 / 808	DPBF↓ ∼18% (12 min); ηPT = 8.95%	808 nm (3 W·cm−2, 30 min) + 420 nm (3 W·cm−2, 8 min)	PDT + PTT	S. aureus, E. coli, MRSA, C. albicans	S. aureus: MIC = 31 µg·mL−1; E. coli: MIC = 16 µg·mL−1	[88]
BDP40	638	DPBF↓ 42.45% (9 min); ηPT = 67.82%	638 nm, 1.0 W·cm−2, 10 min	PDT + PTT	S. aureus, E. coli	>99.5% eradication at 500 µg·mL−1	[89]
BDP41	535	DCFH↑ ∼30‐fold (240 s)	White LED, 50 mW cm−2, 20 min	PDT	S. aureus, E. coli	∼100% eradication at 50 µg mL−1	[90]
PU‐GHB	730	Φ Δ = 0.38; ηPT = 55.9%	808 nm laser, 1.2 W cm−2, 10 min	PDT + PTT	S. aureus, E. coli, MRSA, VRE	>99% eradication	[91]
PBP‐MXene	∼600	ηPT = 34.99%	808 nm laser, 2 W cm −2 + 650 nm xenon lamp	PDT + PTT	S. aureus, E. coli	>99% eradication at 50 µg·mL−1	[104]
BDP43‐ZnO	520 / 790	/	LED, 7W	PDT+ Zn2+ release	S. aureus, E. coli	∼100% eradication of E. coli at 10 µg mL−1, S. aureus at 6 µg mL−1	[106]
BODIPY‐Mo2C	∼500 / 808	ηPT = 42.6%	808 nm laser, 1.5 W cm−2 + 500 nm xenon lamp	PDT + PTT	S. aureus, E. coli	∼100% eradication at 100 µg·mL−1	[105]
BODIPY‐ZIF‐8	465	/	LED, 7W	PDT+ Zn2+ release	S. aureus, E. coli	S. aureus: MBC = 1.25 µg·mL−1; E. coli: MBC = 2.5 µg·mL−1	[29]
BCu NPs	498	DPBF↓ ∼90% (100 s)	Green LED, 18 mW cm−2, 6 min	PDT	S. aureus	MIC = 0.6 µM	[108]

^a Φ _Δ, singlet oxygen quantum yield; η_PT, photothermal conversion efficiency; DPBF, 1,3‐diphenylisobenzofuran; ICG, indocyanine green; DCFH, 2′,7′‐dichlorodihydrofluorescein; ↑/↓ denotes increase/decrease in absorption or fluorescence.

^b Wavelength, power density, and irradiation time.

^c S. aureus, Staphylococcus aureus; E. coli, Escherichia coli; C. albicans, Candida albicans; MRSA, methicillin‐resistant S. aureus; MDR, multidrug‐resistant; VRE, vancomycin‐resistant Enterococcus.

^d MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration.

6. Conclusions and Perspectives

In the face of the global AMR crisis, antibacterial phototherapy has emerged as a non‐antibiotic strategy with distinct advantages. BODIPY derivatives, by virtue of their excellent photophysical properties, high molar extinction coefficients, and highly tunable molecular architecture, have expanded beyond their traditional role as fluorescence imaging probes to serve as multimodal antibacterial platforms integrating both PDT and PTT functionalities. This review systematically summarizes the research advances over the past five years in BODIPY‐based antibacterial phototherapy, encompassing molecular engineering, nanodelivery systems, and bacteria‐targeted design, while also providing perspectives on the challenges and future directions in this field.

The core of BODIPY‐based antibacterial phototherapy lies in the precise mapping of molecular design features onto therapeutic outcomes through structure‐activity relationships. At the molecular level, heavy‐atom doping directly enhances SOC to boost ISC and thus ROS generation, although potential dark toxicity remains a concern; heavy‐atom‐free SOCT‐ISC strategies reconcile efficient triplet formation with improved biosafety, yet both approaches predominantly operate via the Type II mechanism and are therefore less effective in hypoxic infection sites. To achieve PTT, the incorporation of intramolecular rotors such as TPA or the engineering of J‐aggregates efficiently promotes non‐radiative decay, with aza‐BODIPY scaffolds offering an additional advantage owing to their lower fluorescence quantum yield, which favors thermal deactivation; however, achieving high PCE typically relies on precise aggregation‐state stabilization within nanoassemblies, adding formulation complexity. NIR activation for deep‐tissue therapy is accomplished by extending the π‐conjugation system or constructing aza‐BODIPY scaffolds, which narrow the HOMO‐LUMO gap and red‐shift absorption; yet this spectral shift frequently compromises ROS generation efficiency as a result of the Energy Gap Law, demanding a careful balance between wavelength and photodynamic activity. At the nanoscale level, cationization and alkyl‐chain engineering dramatically strengthen electrostatic binding to bacterial surfaces and biofilm penetration, but permanent positive charges may lead to nonspecific cytotoxicity; this limitation can be mitigated by microenvironment‐responsive activation, ligand‐mediated targeting, and gas‐coupled systems that confine or amplify their phototherapeutic action at the infection niche. These systematic structure‐activity correlations not only clarify the current design landscape, but also constitute an actionable roadmap toward next‐generation BODIPY photosensitizers.

Looking ahead, research on BODIPY‐based antibacterial phototherapy should focus on the following frontier directions: developing Type I and NIR‐II photosensitizers to overcome hypoxia and penetration depth limitations simultaneously; constructing intelligent nanoplatforms that integrate diagnostics, therapy, and monitoring to achieve microenvironment‐responsive synergistic enhancement of “PDT + PTT + immunotherapy/gas therapy”; advancing the translation from bench to bedside, including the establishment of standardized light dosimetry protocols, the development of portable smart light‐source dressings, the construction of clinically relevant 3D biofilm/tissue infection models, and the refinement of long‐term biosafety and metabolic assessments; and leveraging artificial intelligence and machine learning to accelerate the high‐throughput screening of novel BODIPY photosensitizers and the elucidation of structure‐activity relationships. Through the deep integration of chemistry, materials science, microbiology, medicine, and computational science, BODIPY‐based phototherapy holds great promise for playing a pivotal role in the “post‐antibiotic era”, providing a powerful weapon in the fight against drug‐resistant bacterial infections.

Author Contributions

Li Lv: writing – original draft, investigation. Heejeong Kim: investigation, writing – original draft. Hongchen Zhai: investigation, writing – original draft. Hanqi Ren: validation, software. Silu Wang: validation, software. Cong Sun: investigation, validation. Yafu Wang: investigation, validation. Hosoowi Lee: writing – review and editing, validation, software, and funding acquisition. Juyoung Yoon: conceptualization, writing – review and editing, funding acquisition, and supervision. Hua Zhang: conceptualization, writing – review and editing, funding acquisition, and supervision.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Li Lv obtained his master's degree from Xuzhou Medical University in 2024. He is currently conducting his doctoral research under the guidance of Professor Hua Zhang at Henan Normal University. His main research focuses on the design and synthesis of organic fluorescent dyes, as well as the development of novel functionalized fluorescent materials for fundamental and applied research related to bioimaging and phototherapy.

Heejeong Kim graduated from Ewha Womans University in 2020 with a bachelor's degree and is currently pursuing a doctoral degree at the same university under the guidance of Professor Juyoung Yoon. Her main research focuses on the design and construction of supramolecular nanomedicines and the development and application of AIE therapeutic drugs, dedicated to fundamental research and cutting‐edge exploration in these fields.

Hongchen Zhai began to pursue a doctoral degree under the guidance of Professor Hua Zhang of Henan Normal University in 2022. His research mainly focuses on the molecular design, synthesis, and development of activatable photosensitizers, nanoprobes, and multifunctional therapeutic agents, with a particular emphasis on the construction and application exploration of novel functionalized diagnostic and therapeutic reagents.

Hanqi Ren began to pursue a master's degree under the guidance of Professor Hua Zhang of Henan Normal University in 2024. Her main research direction is the synthesis and application research of organic small‐molecule fluorescent dyes.

Silu Wang began to pursue a master's degree under the guidance of Professor Hua Zhang from Henan Normal University in 2025. Her research mainly focuses on the design, synthesis, and application research of organic small molecule photosensitizing dyes, with a particular emphasis on the development and performance investigation of new photosensitizing dyes.

Cong Sun began to pursue a master's degree under the guidance of Professor Hua Zhang from Henan Normal University in 2025. Her main research direction is the synthesis and application research of PET‐type organic small molecule photosensitizing dyes.

Yafu Wang obtained her doctoral degree from Henan Normal University in 2022, under the guidance of Professor Hua Zhang. Her research focuses on the enhancement of dye functions and their applications in the field of biomedicine. She has theoretical foundations and research experience in the design and synthesis of electronically controlled fluorescent dyes and fluorescence/planar polarized biological imaging.

Hosoowi Lee obtained her doctoral degree from Yonsei University in 2021, focusing on porphyrin‐based supramolecular polymers. After postdoctoral research at Yonsei and Institut Charles Sadron‐CNRS, she joined Ewha Womans University as a Research Professor in 2024. Her current research focuses on the development of novel photosensitizers for advanced photodynamic therapy.

Juyoung Yoon an outstanding professor in the Department of Chemistry and Nanoscience at Ewha Womans University. In 1994, he obtained a doctoral degree from Ohio State University. Subsequently, he completed his postdoctoral research at the University of California, Los Angeles, and the Scripps Research Institute. His main research focuses are on fluorescence imaging, phototherapy, and integrated research on diagnosis and treatment. Since 2014, he has continuously been included in the list of highly cited researchers in the field of chemistry.

Hua Zhang a professor at Henan Normal University, is a recipient of the National Excellent Young Scientist Fund, an outstanding expert in Henan Province, and an academic and technical leader in Henan Province. Her research focuses on the synthesis of novel functional organic dyes and their applications in spectral analysis, imaging, and treatment. She has published innovative works in internationally renowned academic journals such as Chem. Soc. Rev., Angew. Chem. Int. Ed., and Chem. Sci.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.