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. 2025 Dec 13;6(1):166–178. doi: 10.1021/jacsau.5c01016

Organic Heterojunction Nanoparticles: Photoinduced Charge Transfer and Melanin-Amplified ROS Generation for Melanoma Photodynamic Therapy

Quanyi Jin †, Haoyi Wu †, Wei Zheng †, Qian Lin †, Beibei Liu †, Aijuan Kuang †, Sicong Wang §, Haining Tian §,*, Xuan Zhu †,*, Aijie Liu †,‡,∥,*
PMCID: PMC12848670  PMID: 41614170

Abstract

Melanoma is a life-threatening cancer, requiring more effective treatments. Photodynamic therapy (PDT) is a promising approach with favorable biosafety, although its clinical efficacy remains limited. In this work, we developed a nanoplatform combining poly­(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT) and 1-[3-(methoxycarbonyl)­propyl]-1-phenyl-[6.6]­C61 (PCBM), forming PFBT/PCBM (PP) nanoparticles, which contain a type II heterojunction that enables efficient charge transfer (≥97.7%) under irradiation. The resulting PFBT+• and PCBM–• radicals enable the generation of diverse reactive oxygen species (ROS) at high levels, including superoxide, hydroxyl radicals, and singlet oxygen (both type I and II ROS), through efficient electron and hole transfer processes. These multiple ROS species culminate in potent antitumor activity in vitro and in melanoma-bearing mice. Importantly, endogenous melanin accelerated the photocatalytic cycle, further amplifying the generation of ROS, thus enhancing the therapeutic outcome. Furthermore, PP-based PDT also demonstrated promising results in combating postsurgical infection and supporting wound healing, highlighting its potential as a multifunctional tool for comprehensive melanoma management. This work presents a PFBT/PCBM (PP) nanoplatform formed by coassembling poly­(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT) and PCBM to achieve highly efficient photoinduced charge transfer efficiency (≥97.7%). The resulting PFBT+• and PCBM–• radicals enable the generation of diverse reactive oxygen species (ROS) at high levels, while endogenous melanin accelerates the photocatalytic cycle, further amplifying the generation of ROS and enhancing the therapeutic outcome.

Keywords: heterojunction, photocatalysis, photoinduced charge transfer, photodynamic therapy, melanoma treatment

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Introduction

Melanoma is responsible for 1.7% of cancer incidents with over 330,000 cases and 0.6% of mortality with over 58,000 cases globally in 2022. Although comprising only 2% of skin cancer cases, melanoma is reported to cause 80% of skin cancer death. Surgery still being the primary method of managing early-stage and some locoregional metastases of melanoma; incomplete resection and subsequent recurrence remain jeopardies to patients’ health. Therefore, development of powerful adjuvant therapies is still in need in the treatment of melanoma. Photodynamic therapy (PDT) is gaining attention for minimal invasiveness and controllable side effects in cancer management. − PDT, involving introduction of photosensitizers and local irradiation with light, capacitates photosensitizers to harness light energy to produce a high level of cytotoxic molecules, mainly reactive oxygen species (ROS), to eliminate target cells. The therapeutic efficacy has withstood clinical challenges in various tumor types, including nonmelanoma skin tumors, head and neck tumors, esophagus tumors, etc. In the field of melanoma, although promising results in several clinicals encouraged its application, − the nature of melanoma cells per se, i.e., a melanin-rich environment that scavenges ROS and extra high oxygen consumption-induced hypoxia that limits the production of ROS, severely hinders the efficiency of PDT.

A typical photodynamic process starts with photoexcitation of photosensitizers (PSs) from the ground state to a high-energy singlet state (1PS*). Such a state needs to experience an intersystem crossing to a reactive triplet state (3PS*) to deliver energy, either through a type I process (electron transfer) producing ionic radicals or type II (energy transfer) generating singlet oxygens (1O2). , Currently, prevailing PDT strategies are mostly type II-based, which depend heavily on oxygen concentration. On the contrary, in the less exploited type I process, requirement of oxygen is alleviated for its recycling process, , and hence it is favorable in hypoxic environments like melanoma. Additionally, most of the current attempts to improve the efficacy of PDT focus on extending lifetimes of 1PS*/3PS* or promoting efficient intersystem crossing, i.e., almost entirely depending on abundant exposure time of 3PS*. , Although the efforts in augmenting the fraction of 3PS* have been gaining ground in the field, − relevant studies usually demand systematic and sophisticated molecular design in organic chemistry and sometimes include other therapeutic modes. Moreover, the limited efficiency of intersystem crossing innately inhibits the maximization of PDT effects. Therefore, circumventing this traditional process might be a step forward in the field of PDT.

Linear conjugated polymers are a family of polymeric organic compounds known for efficient light absorption, biocompatibility, high emission quantum yield, and facile structure adjustment, and hence, are currently applied in bioimaging and phototherapies. Prone to stack or interact with other molecules, conjugated polymers are also suitable as doped functional components in heterologous constructs. A fullerene derivative, 1-[3-(methoxycarbonyl)­propyl]-1-phenyl-[6,6]­C61 (PCBM), innately possessing an oxygen reduction activity in electrochemistry, was studied to fully quench the fluorescence of photosensitive polymer dots based on poly­(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT) via charge separation. Such doping enables direct electron transfer from photoexcited PFBT* to PCBM via formation of excitonic polarons, allowing various redox reactions among electrons and holes, ,, and might be a promising strategy to fully store photo energy for chemical reactions and provide a shortcut to substrates compared with traditional triplet-state-dependent routes. Recently, a heterojunction nanoparticle (NP) system combining PFBT as an electron donor and PCBM as an electron acceptor has been reported to efficiently produce hydrogen peroxide (H2O2) with a high quantum yield, strengthening this heterojunction system as an eligible candidate for a powerful PDT platform. Moreover, in melanoma with abundant dopa- or cysteinyldopa-derived melanin pigments with highly reductive polyphenolic structures, this platform might preoccupy melanin with oxidative holes and further facilitate a constant generation of ROS with a steady consumption of holes by melanin to result in a continuous redox cycle.

Herein, we report our attempt to adopt the heterojunction as a PDT nanoplatform in melanoma treatment. We first constructed PFBT/PCBM (PP) heterojunction-based binary NPs stabilized by a polystyrene–polyethylene (PS–PEG) surfactant, accommodating the system to biological applications (Scheme ). The photophysical properties of PFBT and PP NPs were systematically investigated using femtosecond transient absorption spectroscopy. The results indicated that the proportion of long-lived species (>5 ns) in the PP heterojunction was approximately 3-fold greater than that of unary PFBT NPs, promoting diffusion-limited reactions such as oxygen reduction. Building on this insight, we then investigated PP NPs’ capacity to generate multiple ROS species under photoexcitation and systematically assessed their intracellular behavior, biosafety in the dark, and mechanistic pathways of cytotoxicity. Comparative studies against different types of cancer cells revealed that endogenous melanin plays a stimulatory role in photocatalytic cycles, amplifying ROS production and thereby enhancing therapeutic efficacy in melanoma treatment. Finally, in vivo studies demonstrated antitumoral, antibacterial, and wound healing performances of PP NPs in mouse models, underscoring their utility for comprehensive postsurgical melanoma management. Taken together, these findings highlight PP NPs as a robust and multifunctional PDT nanoplatform, with melanin-amplified ROS generation making them particularly well-suited for melanoma management.

1. Illustrations of the Formation, ROS Generation Rationale and PDT Application in Melanoma of PP NPs.

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Results and Discussion

Preparation and Characterization of Heterojunction PP NPs

The heterojunction NPs, coded as PP NPs, that contain donor polymer PFBT and small molecule acceptor PCBM were fabricated with a typical nanoprecipitation method as reported before (Figure A). Briefly, PFBT, PCBM, and surfactant PS–PEG were separately prepared as tetrahydrofuran (THF) stock solutions. The stocks were mixed, sonicated, and rapidly poured into water, and the final NPs were obtained after the vaporization of THF and washing steps. Transmission electron microscopy (TEM) image revealed a spherical morphology of the as-prepared NPs (Figure B). Complementarily, a high-resolution TEM (HR-TEM) image was also obtained, showing an amorphous spherical nanostructure (Figure S1), indicating a homogeneous mixture between donor PFBT and acceptor PCBM, consistent with our previous results. The elemental mapping further confirmed the constituents of the NPs (Figure S2). The hydrodynamic diameter of PP NPs was 113.7 nm with a polydispersity index (PDI) of 0.2 (Figure C), and the zeta potential remained slightly negative, consistent with both of its components (Figure D). The more negative ζ-potential of PFBT/PCBM NPs compared to PFBT NPs or PCBM NPs was observed; this may arise from variations in the packing and conformation of PS–PEG at the particle interface, as neutral PEG layers are known to influence ζ-potential depending on grafting density and organization. , The mixed PFBT/PCBM interface may enhance PS–PEG packing per particle, thus resulting in a slightly more negative ζ-potential compared with unary particles. The sizes and PDIs of PP showed no visible change over 7 days in either water or PBS dispersants (Figure E) and remained stable in different plasma concentrations (Figure S3), indicating good colloidal stability. These results provide supporting evidence of the suitability of PP for subsequent in vivo therapeutic applications.

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Preparation and characterization of PP NPs. (A) Scheme of PP NP preparation. (B) TEM image of PP NPs. (C) The hydrodynamic diameter of PP NPs. (D) Zeta potentials of PCBM, PFBT, and PP NPs (n = 3). (E) The hydrodynamic diameter changes of PP NPs in different media over 7 days (n = 3). (F) UV–vis absorption spectra of PCBM, PFBT, and PP. (G) Fluorescence emission spectra of PFBT, PCBM, PP, and a mixture of PFBT + PCBM NPs, excited at λ = 450 nm.

The ultraviolet–visible (UV–vis) spectrum of PP NPs presented characteristic peaks in that of PCBM and PFBT with slight red shifts (Figure F), indicating coexistence and interactions of two components in the binary NPs. The steady-state emission was then investigated for PFBT alone and in the presence of PCBM in binary NPs. The initial photosensitive properties of PFBT absorb light at 450 nm and emit strong fluorescence with a peak at 550 nm. PCBM almost completely quenched (with an efficiency >97.7%) the original emission of PFBT in the heterojunction (Figure G), while their UV–vis absorbance stayed at a similar level. No fluorescent quenching was observed in the mixed solution of PFBT and PCBM NPs, indicating that the interparticle distance was too large to enable photoinduced charge transfer (Figure G, purple dashed line). Since bare PCBM exhibited negligible absorbance in the wavelength range of 500–700 nm, and sufficient spectral overlap of donor emission and acceptor absorption is determinant to Förster resonance energy transfer efficiency in theory, energy transfer from the excited PFBT (PFBT*) to PCBM was considered negligible in the quenching of the fluorescence. Moreover, considering the observed homogeneity of both components, the subpicosecond charge transfer behavior we previously captured in a similar heterojunction system, and the favorable energy level alignment between these two, the high fluorescent quenching efficiency of PFBT by PCBM is primarily attributed to the charge transfer process from PFBT* to PCBM. This interaction was further strengthened with time-resolved fluorescence spectroscopy (Figure S4), which revealed a notably shorter fluorescence lifetime for the binary PP NPs compared to unary PFBT NPs.

Photophysical Properties of Heterojunction PP NPs

To gain deeper insight into the photoinduced electron transfer mechanism of PP NPs (Figure A), we performed femtosecond transient absorption spectroscopy (fs-TAS) with a probing range of 580–890 nm. Spectroelectrochemical analysis was conducted to support the study, as shown in Figure B, and oxidized PFBT (PFBT+•) exhibited a broad positive absorption from 515 to 1000 nm with a peak around 680 nm.

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Time-resolved absorption spectra of PFBT NPs and PP NPs. (A) Scheme of energy levels of the PP heterojunction. (B) Spectroelectrochemical analysis of PFBT under 1.5 V vs Ag/AgCl. 1030 beam for 450 nm excitation of PFBT, full spectra of (C) PCBM NPs, (D) PFBT NPs, and (E) PP NPs. Spectra at selected time points of (F) PFBT NPs and (G) PP NPs at various time points; decay kinetics at 750 nm of (H) PFBT NPs and (I) PP NPs.

A 1030 nm fundamental pulsed beam was used to generate a 450 nm pump to excite PFBT, PP, and PCBM NPs. As shown in Figure C, PCBM displayed no detectable transient signal within the probed spectral window, whereas PFBT exhibited a photoinduced absorption (PIA) band ranging from 650 to 890 nm, with a maximum near 890 nm (Figure D,F). In the PP heterojunction, however, an intense positive peak centered at 750 nm appeared immediately after excitation (Figure E,G). This feature arises from overlapping contributions of the intrinsic PIA of PFBT and the PFBT+• cation-radical band, consistent with the rapid formation of a nearby charge-transfer pair (PFBT+•–PCMB–•). This peak gradually blue-shifted to approximately 680 nm within 5 ns, corresponding to PFBT+•, as confirmed by spectroelectrochemical analysis (Figure B). To further elucidate the advantages of the PP heterojunction over unary PFBT NPs, decay kinetics at 750 nm were monitored. As shown in Figure H,I, PP exhibits a much faster decay of the photoexcited charges at the early picosecond time scale, indicating the highly efficient charge transfer in this D–A system, followed by slower charge separation and/or diffusion processes, and completed within the nanosecond time scale. Fitting of the transient decay curves using an infinite-time approximation (detection limit = 5 ns) revealed a significantly larger proportion of long-lived species in PP (30.9%) compared to PFBT (9.7%). The increased lifetime fraction further demonstrates enhanced charge separation and reduced recombination in the PP heterojunction, which is expected to promote diffusion-limited redox processes that occur over the microsecond time scale, − such as oxygen reduction.

ROS Generation Behavior of Heterojunction PP NPs

As illustrated in the previous section, PFBT is able to be photoexcited to excited state (PFBT*) under illumination, which, in the heterojunction PP NPs, transfers electrons to PCBM, producing reduced PCBM (PCBM–•) and oxidized PFBT (PFBT+•), and allowing various redox reactions to occur (Figure A). We here systematically studied the ROS generation ability of heterojunction PP NPs. Superoxide (O2 •–) can be converted from oxygen molecules (O2) by PFBT* and/or electron accepted PCBM–• upon photoexcitation. With the ability of dihydrorhodamine 123 (DHR123) to emit green fluorescence when selectively oxidized by O2 •–, we were able to probe the generation of a compound from O2 •–. As anticipated, the heterojunction PP NPs generated the highest level of O2 •– under irradiation compared with other groups, including photoexcited PFBT NPs alone and a mixed solution of PFBT and PCBM NPs (PFBT + PCBM), since PCBM as an electron acceptor in the heterojunction enables prolonging the lifetime of free charges, thereby drastically accelerating the reduction of O2 (Figure B).

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Detection of ROS generated by PP NPs. (A) The rationale of ROS generation by PP NPs. (B) Fluorescence intensity of DHR123 (λex = 450 nm, λem = 525 nm) in various groups. (C) UV–vis absorbance of TMB at λ = 652 nm in various groups. (D) Fluorescence intensity of ABDA (λex = 380 nm, λem = 425 nm) in various groups. (E) ESR spectra of photoexcited PP NPs coincubated with DMPO in water, DMPO in DMSO, and TEMP in water after irradiation for 10 min. (F) Fluorescence intensity of ABDA coincubated with PP NPs prepared with various PFBT:PCBM ratios after irradiation for 10 min. ROS generation of photoexcited PP NPs at various pH. (G) Fluorescence intensity of DHR123 (λex = 450 nm, λem = 525 nm); (H) UV–vis absorbance of TMB at λ = 652 nm; (I) fluorescence intensity of ABDA (λex = 380 nm, λem = 425 nm).

Next, O2 •– is able to be reduced in the presence of protons to generate hydroxyl radical (•OH) through hydrogen peroxide as an intermediate at lower reduction potentials. With a selective probe, tetramethylbenzidine (TMB), we also detected the generation of •OH (Figure C). Meanwhile, the leftover hole polaron, PFBT+•, potentiates oxidation of O2 •– into 1O2, which can be verified by a 1O2 probe, 9,10-anthracenediyl-bis­(methylene)­dimalonic acid (ABDA) (Figure D), consistent with previous findings. Among all of the tested ROS species, the PP heterojunction exhibited the highest generation efficiency, outperforming all control groups. Notably, under the experimental conditions, the temperature of solutions increased by less than 2 °C after 10 min of continuous white light irradiation at a power density of 100 mW/cm2 (Figure S5), confirming that the observed ROS generation was not influenced by thermal effect. In principle, ROS could also be generated by charge transfer from the unquenched photoexcited PFBT*. However, due to the efficient oxidative quenching of PFBT by PCBM (Figures G and S4), this pathway should not contribute much to the ROS formation. The generation of these three types of ROS species was further supported by electron-spin resonance (ESR) spectra, where typical peaks of each species were clearly detected (Figure E). Here, a complete redox cycle was formed to continuously produce ROS, where PCBM–• provides electrons received from photoexcited PFBT*, which are prepared for the next electron acceptance; PFBT+• oxidizes substrates, releasing holes to sustain the photoexcitation process. By comparing relative ABDA intensities, the PFBT:PCBM ratio in the PP heterojunction was settled at 1:2 in the following experiments to maximize ROS-producing efficiency (Figure F).

To further demonstrate the efficient ROS generation capability of our PP heterojunction nanoplatform, we compared its performance with that of the widely used PDT photosensitizer, chlorin e6 (Ce6). , To allow a fair performance comparison, both PP NPs and Ce6 were irradiated under white light with identical concentrations, light doses, and exposure times; this setup reflects realistic therapeutic conditions. The generation rate of all three ROS species of the PP heterojunction surpassed that of Ce6 by 2–3 times (Figure S6), highlighting the superior ROS generation efficiency enabled by the heterojunction-mediated photoredox design.

Additionally, ROS generation experiments under various pH conditions (pH 4, 5, 6, and 7) revealed slight increases in all three species at lower pH values (Figure G–I). This observed pH sensitivity might be attributed to proton-coupled electron transfer in reactions such as •OH and H2O2 formation, which drives a “pH-dependent” like conversion of O2 into ROS. Thus, acidic environments enhanced the generation of O2 •–, •OH, and 1O2, thereby accelerating the entire redox cycle and promoting the overall efficiency of the system. Notably, the ability of PP NPs to favor ROS generation under acidic conditions is highly advantageous for tumor therapy, as the tumor microenvironment (TME) is characterized by extracellular acidosis compared to normal tissues. , This intrinsic compatibility between PP NP’s pH-responsiveness and the pathological TME ensures more efficient and selective ROS-mediated therapeutic activity.

Internalization and Intracellular ROS Generation of Heterojunction PP NPs

To capacitate PP NPs in biomedical scenarios, we inspected the cellular uptake behavior of the nanoparticles first. PP NPs were labeled with indocyanine green (ICG) and coincubated with a melanoma strain, B16F10, for various time periods. By monitoring the emission signals of ICG, we utilized confocal laser scanning microscopy (CLSM) and flow cytometry to observe that PP NPs were gradually internalized over time, with the signals increasing linearly during the first 8 h (Figures A, S7).

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Cell internalization, intracellular ROS, and cell viability after PP-based PDT with or without the existence of melanin. (A) CLSM images of B16F10 cells internalizing ICG-labeled PP NPs (blue, DAPI; red, ICG). (B) CLSM images of B16F10 cells stained with DCFH-DA (green) and MFI quantification (n = 3 wells). (C) CCK-8 assay-based cell viability of B16F10 cells treated in various groups (n = 4 wells). (D) CLSM images of B16F10 cells stained with Calcein-AM (green) and PI (red) and corresponding MFI quantification (n = 3 wells). (E) Structure of melanin, images of melanoma cell pellets compared with other no melanin cells and schemes of ROS production of PP NPs with existence of melanin. (F) Fluorescence intensity of DHR123 (λex = 450 nm, λem = 525 nm) with photoexcited PP NPs with or without melanin coincubation. (G) UV–vis absorbance of TMB at λ = 652 nm with photoexcited PP NPs with or without melanin coincubation. (H) CCK-8 assay-based cell viability of various tumor cells treated with photoexcited PP NPs (n = 4 wells). (I) Flow cytometric analysis of DCFH-DA stained various tumor cells treated with photoexcited PP NPs at the concentration of 0, 20, and 40 μg/mL. Note: I: PCBM-Dark; II: PCBM-Light; III: PFBT-Dark; IV: PFBT-Light; V: PP-Dark; VI: PP-Light. Student’s t test, *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.

Next, we moved forward to investigate the ROS-generation capability of the internalized PP NPs at the cellular level. 2’-7’-Dichlorodihydrofluorescein diacetate (DCFH-DA) was applied to probe global intracellular ROS levels. An intense emission signal of the probe, nearly undetectable in other groups, was observed in the irradiated PP group through both CLSM and flow cytometry, indicating a substantial elevation of the overall ROS level in the PP-treated cells in the presence of light (Figure B). To further clarify the generated ROS species, dihydroethidium (DHE), coumarin-3-carboxylic acid (3-CCA), and singlet oxygen sensor green (SOSG) were introduced to visualize the intracellular level of O2 •–, •OH, and 1O2, respectively. Similarly, a sharp increase of each species was spotted in the PP group in the presence of light (Figure S8), much higher than other control groups, validating successful promotion of all three ROS species in cells.

In Vitro Tumoricidal Effects of Heterojunction PP NPs against Melanoma

To potentiate ROS-generating PP NPs for PDT, we then investigated the cytotoxicity of our materials. B16F10 cells were treated with PFBT, PCBM, and PP NPs, kept at dark or light illumination, for a typical cell counting kit-8 (CCK-8) cell viability assay. PP NPs demonstrated prominent cytotoxicity toward B16F10 cells compared with either component alone or PP without light (Figure C), indicating a promising PDT effect. This result was also consolidated with a calcein-acetoxymethyl/propidium iodide (Calcein-AM/PI) live–dead double staining assay (Figures D and S9). Similar phototoxicity was also observed against a human melanoma cell line, A375 (Figure S10). Furthermore, complementary cellular experiments, including crystal violet staining and scratch assay, were conducted to evaluate the therapeutic impact of the irradiated PP NPs. Colony formation assays revealed a notable reduction in colony-forming ability, while scratch width measurements demonstrated impaired cell migration (Figure S11), underscoring the effectiveness of the PP-Light group in inhibiting both tumor cell proliferation and motility. Meanwhile, mouse fibroblast L929 cells were also treated with PP NPs at dark. No apparent cell death was observed (Figure S12), guaranteeing the biosafety of PP in normal tissues in vitro.

Encouraged by the above promising results, we proceeded to study whether melanoma exhibits greater sensitivity to PP-based PDT compared to other tumor types. Melanoma cells, exemplified by the B16F10 line, are characterized by abundant melanin expression, visually identifiable by their distinctive black pellets (Figure E). Although melanin has traditionally been regarded as a ROS scavenger that hinders PDT effects, owing to its polyphenolic nature and intrinsic antioxidant capacity, , recent studies have revealed that melanin can also function as a redox mediator to facilitate redox reactions. , The redox potential of melanin (+0.4 V vs NHE) makes it thermodynamically susceptible to oxidation by the photo-oxidized donor PFBT+• (oxidation potential of +1.4 V vs NHE), ,, which provides a sufficient driving force for hole transfer to melanin. In the heterojunction PP NPs, this hole-transfer process enables melanin to accept holes from PFBT+•, thereby relieving hole accumulation and effectively suppressing electron–hole recombination. Concurrently, electrons residing in PCBM are readily transferred to O2, driving the formation of ROS. Thus, this melanin-mediated hole scavenging establishes a closed redox cycle across the heterojunction, prolonging charge separation and amplifying overall ROS generation. Experimental results support this mechanism; upon photoexcitation, PP NPs in the presence of melanin produced higher levels of all three ROS species (Figures F, G, and S13). The photothermal contribution of melanin can be ruled out, as all solutions, including melanin alone, exhibited negligible temperature increases (<2 °C) under continuous light irradiation at 100 mW/cm2 (Figure S5). It is worth noting that the light density used in photothermal conversion study was twice that of extracellular ROS generation experiment (50 mW/cm2), and more than 50-fold higher than that used for intracellular studies (1.5–2 mW/cm2); therefore, thermal effect can be confidently excluded under our experimental conditions. The observed increase in O2 •– production correlates with facilitated electron transfer from PCBM–• to O2, while the generation of 1O2, despite competing with hole polaron processes, was also enhanced by the melanin-assisted redox cycle.

Subsequently, cell viability across various tumor cells was assessed, including HepG2, HeLa, 4T1, PANC1, and HCT116, as well as B16F10, following PP-Light treatments. As expected, while PP-based PDT was cytotoxic toward all studied strains, B16F10 displayed higher susceptibility (Figure H), accompanied also by a much higher intracellular ROS level (Figure I). These results highlight the potential of melanin’s oxidative properties to enhance the therapeutic impact of PP-based PDT, particularly against melanoma.

PP-Based PDT-Triggered Apoptotic Death of Melanoma Cells

To elucidate the tumoricidal mechanism of photoexcited PP NPs, we focused on key characteristics of ROS-induced cell death, including mitochondrial misfunctions, DNA damages, and lipid peroxidization. Mitochondrial health, often reflected by a stable membrane potential, is compromised when this potential is lost, which usually indicates mitochondrial damage and can be detected through the aggregation status of a commercial JC-1 probe. In the PP-Light group, the exacerbated aggregation of JC-1 was observed, indicating a substantial loss of mitochondrial membrane potential and highlighting mitochondrial damages caused by this treatment (Figure A,B). DNA damage was evidenced by elevated levels of γ-H2AX, as demonstrated through both immunofluorescence staining and Western blotting (WB), further confirming DNA damage in PP-Light group treated B16F10 cells (Figures C,D and S14). Additionally, elevated signals from oxidized BODIPY-C11 and malondialdehyde (MDA) probes revealed promoted lipid peroxidation following PP-Light treatment compared with control groups (Figure S15). Collectively, these results indicate that the excessive level of ROS generated by PDT inflicts damage on mitochondria, DNA, and lipid membranes, leading to cellular dysfunction.

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Mitochondrial damage, DNA damage, and apoptotic pathway investigation of PP-based PDT. (A, B) CLSM images of JC-1 stained B16F10 cells (blue, DAPI; red, JC-1 monomer; green, JC-1 aggregates) and MFI quantification (n = 3 wells). (C, D) CLSM images of γ-H2AX immunofluorescence stained B16F10 cells (blue, DAPI; cyan, immunofluorescence signal of γ-H2AX) and MFI quantification (n = 3 wells). (E–H) WB images of various proteins from treated B16F10 cells. (I) Scheme of PDT-triggered apoptosis. Student’s t test, ****p < 0.0001.

To further clarify the mechanism of cell death, we conducted viability assays using cells coincubated with PP-Light group treatment and four known cell death inhibitors. Notably, only the apoptosis inhibitor, Z-VAD-FMK, highly rescued cells from death (Figure S16A), indicating apoptosis as the primary mode of cell death in PP-based PDT. Since PDT-triggered cell death is widely accepted to experience canonical apoptosis, with a cell apoptosis kit, i.e., Annexin-FITC/PI double staining, we found an increase of late apoptotic cell group with irradiated PP treatment in a concentration-dependent manner (Figure S16B–C). An intrinsic apoptotic route of PDT was reported to be initiated with ROS-related mitochondrial damage, which was consistent with the aforementioned phenomena. Traversing through the entire pathway, we checked the levels of each participating protein with WB. We found an upregulation of each pro-apoptotic species, including cleaved Caspase-3, cleaved Caspase-9, cleaved PARP, Bax, and Cytochrome C (Figure E–G), along with downregulation of antiapoptotic species Bcl-2 (Figure G) in PP-Light group-treated cells. Next, we evaluated Fas and Caspase-8 levels; WB imaging results demonstrated their notable elevation, indicating that the extrinsic pathway also contributes to cell death (Figures H and S17), consistent with former reports. Overall, these findings demonstrate that PP-based PDT induces a classic apoptotic cell death mechanism driven by ROS-related mitochondrial damage, DNA fragmentation, and lipid peroxidation. The upregulation of pro-apoptotic signals and the involvement of both intrinsic and extrinsic pathways highlight the multifaceted and potent nature of PP-based PDT in triggering tumor cell apoptosis (Figure I).

In Vivo Melanoma Therapeutic Effects of Heterojunction PP NPs-Based PDT

We then continued to evaluate in vivo antitumoral efficacy of heterojunction PP-based PDT. Prior to the study, PP NPs were incubated with mice blood to briefly assess the biocompatibility. Across all studied concentrations, hemolysis levels, indicated by heme absorbance, remained below 5% of the water positive control (Figure S18), confirming negligible hemolysis and excellent biocompatibility. Additionally, organic heterojunction structures themselves might succumb to oxidation by ROS, leading to degradation over time. This photodegradability was presented by recording the UV–vis spectra of PP NPs upon irradiation, both with or without 10 mM glutathione (GSH) to mimic the intracellular environment (Figure S19). Within 72 h, GSH drastically accelerated photodegradation of PP NPs, while the absorbance in the GSH-free group weakened negligibly, suggesting the facilitating role of reductive GSH to ROS generation similar to melanin. This was supported by the higher ROS generation that was observed with increasing GSH concentration, ranging from 2 mM to 40 mM (Figure S20). The data exhibited photostability of PP NPs in a regular environment and self-destructive degradability in a therapeutic scenario, both of which are clinically friendly traits.

On this basis, we further investigated the biodistribution and in vivo antitumor activity of PP. Wistar rats were intravenously injected with ICG-labeled PP, and pharmacokinetic analysis was performed by calculating the blood ICG concentration at different time points based on fluorescence intensity. The ICG-labeled PP exhibited a prolonged plasma circulation time in vivo (Figure S21). The in vivo tumor suppression study was carried out using C57BL/6J mice with a subcutaneous B16F10 melanoma model. Tumor-implanted mice were divided into eight groups and received intratumoral administration of PBS, PFBT alone, PCBM alone, or PP NPs every 2 days, followed by irradiation or no irradiation (Figure A). Tumor sizes and body weights were monitored over the 12-day treatment duration. Remarkably, the PP-light group demonstrated superior tumoricidal efficacy, outperforming all other groups, including its components alone under irradiation and nonirradiated counterparts (Figure B–D). The tumor inhibition rate for the PP-light group treatment reached an impressive 90% (Figure D and Figure S22), with negligible body weight loss (Figure E), highlighting the robust therapeutic potential of PP-based PDT. Histological analysis of tumor tissues collected post-treatment provided additional evidence of the therapeutic effect. Hematoxylin–eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining revealed extensive tumor cell death in the PP-light group (Figure F–H), corroborating its potent antitumoral activity.

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In vivo PDT antitumoral efficacy of heterojunction PP NPs. (A) Scheme of the entire treatment timeline. (B) Images of dissected tumors after treatment. (C) Records of tumor volume changes (n = 4 mice). (D) Weights of dissected tumors after treatment (n = 4 mice). (E) Body weight records of treated mice (n = 4 mice). (F) Images of H&E-stained tissues from dissected tumors. (G, H) Images of TUNEL-stained tissues from dissected tumors and MFI quantification (n = 3). Note: I: PCBM-Dark; II: PCBM-Light; III: PFBT-Dark; IV: PFBT-Light; V: PP-Dark; VI: PP-Light. One-way ANOVA and Student’s t test, **p < 0.01 and ***p < 0.001.

In addition to its excellent antitumor efficacy, it is also worth mentioning that the ideal biosafety of the treatment was revealed through several parameters. Body weights of treated mice showed minimal fluctuation throughout the treatment (Figure E), while histological examination of major organs confirmed no apparent pathological changes (Figure S23). Moreover, serum biochemical parameters remained within normal ranges, indicating systemic safety (Figure S24). These findings underscore the potential of PP-based PDT as a highly effective and safe therapeutic strategy for melanoma treatment.

As a preliminary exploration of PP NPs’ therapeutic potentials, we also conducted mice fluorescent imaging (6–7-week-old female Balb/c nude mice, B16F10 cells). We compared the biodistributions of ICG-labeled PP NPs and free ICG. The results demonstrated that PP NPs exhibited clear accumulation and retention in subcutaneous tumor tissues (Figure S25), consistent with the behavior of typical nanoscale particles sized between 30 and 200 nm. In contrast, only slight distribution in liver and negligible accumulation in other major organs, including heat, spleen, lung, and kidney, were observed, reassuring the feasibility of systemic administration of PP NPs. Therefore, we further evaluated the therapeutic efficacy of PP NPs in C57BL/6J mice bearing subcutaneous B16F10 melanoma via tail vein administration. Tumor sizes and body weights were monitored over a 10 day treatment period. As shown in Figure S26, the PP-Light group exhibited markedly enhanced antitumor efficacy compared with the PBS group, while no significant differences in body weight were observed between the two groups. This experiment might also be considered a pioneering attempt to design organic heterojunction particles with more precisely targeting ability to cope with more complicated situations, such as metastasis.

Considering that current effective melanoma therapy still primarily relies on surgical resection of the primary tumor. However, surgical tumor removal often necessitates a wide excision margin, resulting in large wounds that might need subsequent tissue reconstructing treatment. Moreover, with the risks of melanoma tissues partially escaping excision, postoperational tumor relapse remains a great concern in real-life practices. To address the critical needs of postoperative melanoma management, including tumor cell inhibition, anti-infection, and wound-healing functions, we further demonstrate the wound-healing potential of heterojunction PP NP-based PDT.

In vitro studies demonstrated that irradiated PP NPs also exhibited a potent antibacterial effect against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA), as evidenced by reduced colony counts (Figure S27) and OD600 values (Figure S28), increased PI emissions (Figure S29), bacterial membrane disruption (Figure S30), and increased intracellular ROS level (Figure S31). In vivo studies demonstrated that irradiated PP-based PDT markedly accelerated healing of MRSA-infected wounds, with the PP + light group showing the best wound-healing performance, as evidenced by reduced wound areas (Figures S32 and S33). Histological analyses further confirmed enhanced tissue regeneration, as revealed by CD31 immunohistochemical staining (Figure S34), H&E staining (Figure S35), and superior collagen deposition (Masson’s trichrome staining; Figure S35), underscoring the dual antibacterial effects with tissue regeneration and offering a compelling solution for postsurgical melanoma wound care.

Conclusion

In melanoma, melanin enrichment has challenged PDT performance due to its antioxidant properties, which quench ROS, thereby reducing the therapeutic efficacy. To overcome this challenge, here we introduce an all-organic heterojunction platform based on PFBT–PCBM binary nanoparticles, which exhibit excellent biocompatibility with superior photochemical performance. This binary nanostructure leverages the inherent charge-transfer properties of donor–acceptor systems, facilitating the spatial separation of photoinduced electrons and holes and enabling sustained redox reactions that bypass conventional pathways for ROS generation and actively deplete intracellular reductants such as melanin and GSH. Meanwhile, the reductive species were exploited in the process to facilitate both Type I and Type II ROS production. Our in vivo studies in melanoma models revealed potent therapeutic effects, indicating that such organic heterojunctions may serve as more biocompatible and versatile alternatives for PDT. Beyond tumor ablation, PP NPs also exhibited potent antibacterial activity and wound-healing-promoting ability, which could benefit postoperative tumor relapse treatment. These findings underscore the versatility of PP NPs in addressing critical challenges associated with melanoma management, including tumor suppression, infection control, and tissue regeneration. Biodistribution studies further confirmed effective systemic delivery of these PP NPs, tumor accumulation, retention, and inhibition, paving the way for future translational studies. With the success of this work, similar donor–acceptor pair strategies might be further explored with different pairing molecules and formulations to meet broader therapeutic needs, including extension to a broader spectrum range (from visible to near-infrared) and more complex biological environments.

Supplementary Material

au5c01016_si_001.pdf (3.3MB, pdf)

Acknowledgments

This work was financially supported by National Nature Science Foundation of China (No. 22302164), the National Nature Science Foundation of China (No. 82273872), Shenzhen Science and Technology Innovation Commission (No. JCYJ20230807091311023), the Natural Science Foundation of Fujian Province (No. 2023J05014), the Fundamental Research Funds for the Central Universities (20720240050), and Jiangxi Provincial Natural Science Foundation (20252BAC200024). H.T. would like to thank the financial support from K&A Wallenberg foundation under Wallenberg Academy Fellow program (2019.0156). We also greatly thank Prof. Xianshao Zhou (HIT) and Prof. Hongwei Song (SCUT) for valuable discussions.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01016.

  • Detailed materials and methods, preparation and characterization of nanoparticles, including HR-TEM, elemental mapping, photoluminescence decay, ROS generation assays, and biological studies and additional references − (PDF)

#.

Q.J., H.W., W.Z., and Q.L. contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. CRediT: Quanyi Jin data curation, investigation, methodology, writing - original draft, writing - review & editing; Haoyi Wu data curation, formal analysis, investigation, methodology, software, writing - review & editing; Wei Zheng data curation, formal analysis, methodology, visualization, writing - review & editing; Qian Lin data curation, methodology, software, visualization, writing - review & editing; Beibei Liu visualization, writing - review & editing; Aijuan Kuang methodology, writing - review & editing; Sicong Wang methodology, writing - review & editing; Haining Tian funding acquisition, supervision, writing - review & editing; Xuan Zhu funding acquisition, supervision, writing - review & editing; Aijie Liu conceptualization, funding acquisition, investigation, supervision, writing - review & editing.

The authors declare no competing financial interest.

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