Photodynamic therapy (PDT) has arisen as a promising method due to its spatiotemporal precision and minimal invasiveness. It encounters significant obstacles in solid tumors due to hypoxia-induced therapeutic resistance and the self-protective mechanisms of cancer cells facilitated by MutT homolog 1 (MTH1), an enzyme involved in oxidative damage repair. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on hollow mesoporous manganese dioxide (H-MnO2) for PDT. This platform utilizes H-MnO2 to produce oxygen (O2) through the decomposition of hydrogen peroxide (H2O2) in TME, thereby mitigating hypoxia and enhancing reactive oxygen species (ROS) generation. The high concentration of glutathione (GSH) and hyaluronidase (HAase) in TME induces the release of CRISPR/Cas9 ribonucleoproteins (RNP) to target the MTH1 gene, thereby impairs oxidative damage repair pathways and amplifys ROS-mediated cytotoxicity. The released Mn2+ ions function as immunomodulatory agents, activate innate immune responses via stimulating STING signal pathway. In vitro, IHMRH NPs markedly increased intracellular O2 levels, ROS production, lipid peroxidation and DNA damage, leading to tumor cell death, immune activation, and effective gene editing. In vivo, the nanoplatform suppressed tumor growth, diminished MTH1 gene expression, stimulated dendritic cell (DC) maturation through immunogenic cell death (ICD). This multimodal nanosystem may amplifies oxidative stress, collaborates with innate and adaptive immune activation to surpass the constraints of traditional PDT. The research presents a novel framework for cancer combination therapy by systematically integrating nanotechnology with precision gene editing.

Cubosomes are non-lamellar lipid nanoparticles that have drawn a significant attention in the field of nanomedicine due to their tunable properties. However, the formation of vesicles during the preparation of cubosomes, and the presence of mixed bicontinuous cubic phases, may lead to artifacts and lack of correlation between the physico-chemical and biological characterization. In this work, we have formulated cubosomes composed by monoolein as building block and triblock copolymer Pluronic® F108 as a stabilizer, encapsulating three porphyrin derivatives: two attached to bile acid moieties and one to a tetrapeptide to be used for potential theranostic applications. First, the effect of the cargo concentration (0.25, 0.50 and 1.00 mg/mL, for all three molecules) was evaluated on the structure, showing that the bile acid derivatives did not affect the self-assembly of the lipid providing only Pn3m phases; however, a mixed phase Pn3m + Im3m and a subsequent loss in crystallinity were induced by increasing concentrations of the tetrapeptide derivative. Overall, the encapsulation of the three molecules at 25 and 37 ∘C did not affect neither the hydrodynamic size nor the polydispersity of the cubosomes, influencing mainly the ζ-potential - positive in the case of the tetrapeptide and negative for the bile acid derivatives. The samples formulated with 0.50 mg/mL exhibited higher colloidal stability over time, with no significant changes in size or ζ-potential for over a month. Interestingly, the formulations containing the bile acid derivatives displayed the typical morphology of cubosomes in solution and a reduced number of vesicles (ca. 60:40 as cubosomes-to-vesicles ratio), whereas the sample containing the porphyrin attached to the tetrapeptide led to a ratio of cubosomes-to-vesicles estimated as 26:74, similar to the results of the empty formulation. The experiments at body temperature highlighted that the structure of the different formulations was not affected in a significant manner with retention of the phases observed at room temperature. The promising physico-chemical properties, especially at body temperature, could make these samples suitable as nanoplatforms for drug delivery applications.

HER2-positive breast cancer, characterized by the overexpression of HER2 receptors, often develops resistance to trastuzumab, limiting its therapeutic efficacy. In this study, we explore the use of photodynamic therapy (PDT) with a trastuzumab-IRDye700DX photoimmunoconjugate (Tz-IR700) as a strategy to overcome trastuzumab resistance. Tz-IR700 combines the antibody's selectivity for the tumoral cells with the cytotoxic effect of IR700, induced by red light. Our results demonstrate that Tz-IR700 selectively accumulates in trastuzumab-resistant HER2-positive tumours (HCC1954) thereby enabling precise tumour localization by fluorescence imaging. Upon irradiation with red light, Tz-IR700 induces significant HCC1954 cell viability reduction both in vitro and in vivo, notably overcoming trastuzumab resistance in this HER2-positive breast cancer cell line. Mechanistic studies unequivocally demonstrate that the primary cytotoxic species is singlet oxygen. These findings suggest that Tz-IR700 could serve as a valuable treatment option for trastuzumab-resistant HER2-positive breast cancer and may also be used as an adjuvant to fluorescence-guided surgery, improving surgical outcomes and reducing the likelihood of tumour recurrence and metastasis.

The diversification of ligands provides more opportunities to adjust the photophysical performance as well as the bio-function of Ru(II) complexes as novel photosensitizers. Herein, a kind of Ru(II) complexes carrying resveratrol derivative, amino-Res, as ligand was designed and synthesized. The representative complex (named Ru4) showed potent anticancer activity under the trigger of 520 nm-light. Lipophilicity and cellular accumulation experiments indicated that Ru4 possessed higher LogPO/W value and cell up-take than Ru1-Ru3 and [Ru(bpy)3]2+. Mechanism study revealed that Ru4 could inhibit cancer cell migration, invasion and cancer stemness. The bio-function of Ru4 was mainly inherited from the amino-Res ligand. The in vivo study demonstrated that Ru4 could inhibit the tumor growth without significant system toxicity.

Currently, the clinical treatment of cancer is mainly based on surgery, chemotherapy and radiotherapy, but there are still problems associated with these treatments, such as disease recurrence and adverse reactions. The complexity and harmful nature of cancer mean that combining multiple treatment methods is an inevitable response. Therefore, it is of theoretical and practical significance to expand upon and study the aforementioned classic and traditional measures. With the advancement of technology, physical therapy has become important in the current research and treatment of cancer, and the physical factors related to cancer deserve in-depth study and discussion. The present review aimed to describe the mechanisms of action of pressure, temperature, photo-, sound and other physical therapies for cancer, which may provide new avenues for cancer treatment.

The combination of chemotherapy and photodynamic therapy (PDT) for enhancing cancer therapeutic efficiency has attracted tremendous attention recently. However, limitations, such as low local concentration and uncontrollable release of therapeutic agents, reduce combined treatment efficacy. In the present study, we engineered a biomimetic nanodrug employing hollow Prussian blue nanoparticles (HPB NPs) to co-load the chemical agent bufotalin (CS-5) and the photosensitizer chlorin e6 (Ce6) for combined chemo/PDT therapy against cancer. HPB NPs with catalase (CAT)-mimetic activity significantly improved the efficacy of PDT by catalyzing the decomposition of H2O2 into O2, thus alleviating hypoxia, which conversely amplified the efficiency of combination therapy. In vivo assay demonstrated that the encapsulation of a hybrid membrane on the HPB NPs prolonged blood circulation life 3.4-fold compared to free drug. Additionally, this strategy of combinational chemo/PDT therapy exhibits a remarkable cytotoxic effect against gastric cancer (BGC-823) and breast cancer (4T1) through the induction of ferroptosis and pyroptosis while simultaneously activating the immune response, with minimal adverse effects on normal organs. Thus, the co-delivery system based on biomimetic nanocarriers appears to be a promising platform for combined chemo/PDT therapy in tumor treatment.

The advancement in exclusively tailored therapeutic delivery systems has escalated a great deal of interest in targeted delivery to augment therapeutic efficacy and to lessen adverse effects. The targeted delivery approach promisingly helps to surmount the unmet clinical needs of conventional therapies, including chemoresistance, limited penetration, and side effects. In the case of melanoma, various receptors were overexpressed on the tumor site, among which folate receptor (FR) targeting is considered to be a progressive approach for managing melanoma. FRs are the macromolecules of the glycosyl phosphatidylinositol-attached protein that possess globular assembly with a greater affinity toward specific ligands. So, the functional ligands can be utilized to design targeted nanocarriers (NCs) that can effectively bind to overexpressed FRs. Hence, folate-adorned NCs (FNCs) offer various benefits such as site-specific targeting, cargo protection, and minimizing toxicity. This review focuses on the insights and implications of FRs, targeting FRs, and mechanisms, challenges, and advantages of FNCs. Further, the applications of various FNCs, such as liposomes, polymeric NCs, albumin nanoparticles, inorganic NCs, liquid crystalline nanoparticles, and nanogels, have been elaborated for melanoma therapy. Likewise, the potential of FNCs in immunotherapy, photodynamic therapy, chemotherapy, gene therapy, photothermal therapy, and tumor imaging has been exhaustively discussed. Furthermore, translational hurdles and potential solutions are discussed in detail. The present review is expected to give thoughtful ideas to researchers, industry stakeholders, and formulation scientists for the efficacious development of FNCs.

Iridium(III) complexes have been recognized as promising candidates for two-photon sensitized photodynamic therapy (PDT). In this context, we report on the study of two complexes: a monomer (IrL1) and a dimer (Ir2L2). Both complexes possess 2-phenylpyridine cyclometallating ligands and a pyridylbenzimidazole derivative as an ancillary ligand. In the dimer, the two Ir(III) centers are connected by a non-conjugated bridged bis(pyridylbenzimidazole). We compare the photophysical properties of these complexes. Both display phosphorescent emission in the orange-red part of the visible spectrum, with emissions centered at 610 nm for IrL1 and 625 nm for Ir2L2, both exhibiting quantum yields of ∼24%. However, Ir2L2 proves to be much brighter than the monomer, making the dimer four times brighter than IrL1. This trend is consistent under two-photon excitation (TPE), and the singlet oxygen generation quantum yields, with the dimer displaying a figure of merit (σTPA × ΦΔ) of 40, compared to only 5 for the monomer. Both complexes generate intracellular ROS and exhibit strong phototoxicity upon blue light activation (λ = 420 nm), achieving submicromolar IC50 values in HT29 and A549 cell lines after 24 h of incubation. Moreover, with TPE (λ = 800 nm), both complexes also generate intracellular ROS and induce cancer cell death.

In recent years, cancer has emerged as a major global health threat, ranking among the top causes of mortality. While treatments such as surgery, immunotherapy, radiation therapy, and chemotherapy remain widely used, photodynamic therapy has been gaining significant interest. Most of the photosensitizing agents employed in clinical settings are derived from tetrapyrrolic frameworks, including porphyrins, chlorins, and phthalocyanines. Although these compounds have demonstrated therapeutic effectiveness, they suffer from critical drawbacks, such as limited solubility in water and inadequate (photo)stability. To address these issues, herein, the formulation of the previously reported and promising photosensitizer tetrakis(4-carboxyphenyl) porphyrin into carbon dots is reported. The carbon dots were found with enhanced aqueous solubility, high (photo)stability, and greater singlet oxygen quantum yield overcoming the limitations of the molecular photosensitizer. While being nontoxic in the dark, the carbon dots induced a phototherapeutic effect in breast cancer cells and multicellular tumor spheroids.

Understanding the relationship between molecular structure and bioactivity is crucial for optimizing porphyrin-based therapeutics. By integrating cheminformatics techniques with machine learning models, our work enables the efficient classification of compounds based on their molecular structures and their growth inhibition capabilities (IC50). A dataset of 317 porphyrin derivatives was compiled, incorporating molecular descriptors and biological activity data. Descriptive statistical analysis was performed to examine compound distribution and key features. Clustering analysis was conducted using hierarchical clustering and fingerprint similarity matrices to classify compounds based on structural similarity. Lipinski's Rule of Five was applied to assess drug-likeness, while Murcko scaffold analysis identified core structural patterns. Tumor response data were analyzed to evaluate therapeutic efficacy. Machine learning models were implemented to predict bioactivity. Descriptive statistics highlighted bioactive compounds, with TMPyP4 and Temaporfin being the most studied. Quantitative estimation of drug-likeness and the number of aliphatic carboxylic acids were identified as the most influential descriptors among others for bioactivity. Hierarchical clustering segmented porphyrins into nine structural groups. The analysis identified 168 pIC50 active compounds, with 31 meeting Lipinski's criteria, and 11 overlapping as both effective and bioavailable. Tumor response analysis revealed three porphyrins achieving 100% response. Logistic Regression emerged as the best-performing model, achieving 83% accuracy, demonstrating robust predictive capabilities. This study successfully characterized porphyrin derivatives, reviewing key molecular features influencing bioactivity and evaluating their therapeutic potential. It highlights the potential of machine learning in predicting the biological activity status of porphyrin derivatives.

Several clinical studies suggest that following surgical resection, intraoperative photodynamic therapy (intraoperative PDT) has the potential to reduce local recurrence and improve overall survival in patients diagnosed with pleural dissemination of lung cancer. The response to intraoperative PDT depends on the light dose rate (irradiance) and dose (fluence) as well as the intratumoral concentration of the photosensitizer and oxygenation. We seek to advance intraoperative PDT by improving the control of irradiance and fluence with image-based treatment planning for an optical surface applicator (OSA) with a novel photosensitizer (TLD1433) that has shown safety in recent clinical trials. To that end, we tested the accuracy of Monte Carlo-based simulations of light delivery from the OSA in vitro and in vivo. We assess the safety and biodistribution after the instillation of TLD1433 in the peritoneal cavity of mice and rats, and define the relationship between the intratumoral irradiance and fluence, and the volume of tumor ablation in the peritoneal cavity of rats. The Monte Carlo simulations agreed with light dosimetry measurements at a 5-mm prescription depth in vitro. An instillation of TLD1433 in the peritoneal cavity of mice is safe and leads to drug accumulation in the tumor and adjacent organs in the peritoneal cavity of rats. A TLD1433-mediated intraoperative PDT procedure using an instilled dose of 14 mg/kg and 532-nm laser light induces tumor cell degradation in the peritoneal cavity of rats. Our results suggest that the Monte Carlo simulation can be used as an image-based treatment plan for administering a controlled PDT procedure with OSA and TLD1433.

Photodynamic therapy (PDT), as a minimally invasive cancer therapy, demonstrates certain advantages in treating superficial tumors. However, it often faces challenges such as low reactive oxygen species (ROS) generation efficiency and non-targeted distribution of photosensitizers. The combination of chemotherapy and PDT can address the limitations of single modal therapies and improve therapeutic outcomes. In this work, we design a prodrug-based nanomedicine that can achieve photo-activated cascade drug release. Under 660 nm laser irradiation, the generated singlet oxygen can trigger the release of chemotherapeutic agent chlorambucil, cinnamaldehyde and quinone methyl. Chlorambucil can exert anti-tumor effects and cinnamaldehyde can increase intracellular hydrogen peroxide levels, while quinone methyl can consume intracellular glutathione. This process ultimately results in the amplification of ROS signals and further activation of prodrugs. This nanomedicine exhibits the ability to amplify oxidative stress and potent anticancer activity. In vivo experiments show that the nanomedicine can effectively inhibit tumor growth. This work provides a promising mutually beneficial strategy for achieving cooperative cancer therapy.

Porphysomes are a class of liposome-like nanoparticles that have demonstrated efficacy in photothermal therapy (PTT) and photodynamic therapy (PDT) against cancer. These nanoparticles results from the self-assembly of amphiphilic phospholipid-porphyrin (PL-Por) conjugates. Despite their potential, porphysomes exhibit a high photothermal effect and a weak photodynamic activity as long as they remain intact within the body. In this study, we present the design of a novel generation of smart porphysomes capable of undergoing active dissociation and releasing porphyrin moieties upon illumination, thereby enabling tunable photothermal properties with enhanced photodynamic efficiency. These new porphysomes are composed of smart PL-Por conjugates that exhibit one or two ROS-responsive linkers separating the polar head group from the porphyrin moiety. Among the designed molecules, we demonstrated that monosubstituted conjugates bearing either pyro-a or pheo-a porphyrinoids with one ROS-responsive bond and shorter linker showed the best performance in terms of stability, photothermal and photodynamic efficiencies in vitro. Moreover, these assemblies were found to achieve complete tumor ablation in 80 % of PC3 prostate subcutaneous tumor-bearing mice after 30 days post-PDT, compared to 0 % using conventional porphysomes. Consequently, our strategy enabled the development of a versatile platform for delivering porphyrin-based photosensitizers for enhanced photodynamic applications.

This study aimed to study the effect of combined antimicrobial photodynamic therapy (aPDT) and photobiomodulation therapy (PBMT) in the management of recurrent herpes labialis (RHL). Sixty participants were randomly assigned into three groups. Group 1 (control): 5% Acyclovir was applied as a topical cream, and a non-activating laser was applied. Group 2 (PBMT): PBMT was applied using a low-level laser therapy (LLLT) and a placebo cream. Group 3 (aPDT + PBMT): aPDT using 0.1% methylene blue with PBMT and a placebo cream. A laser diode emitting light at a wavelength of 650 nm and a power output of 100 mW was applied to each spot for 120 s. The parameters of aPDT were a wavelength of 650 nm, with power and energy density parameters set at 100 mW/ 0.1 W and 24 J/cm², respectively. Pain intensity was measured using a visual analog scale (VAS). At the baseline (t0). After applying the laser (t1). After 48 h (t2). After utilizing the laser in the second session (t3). After 7 days (t4). The point of healing was the spontaneous shedding of the crust. The aPDT + PBMT group outperforms the control group in reducing pain intensity at t1 (p = 0.011), t2 (p = 0.041), and t3 (p = 0.005). In addition, the aPDT + PBMT group outperformed the PBMT group at t3 (p = 0.020). aPDT + PBMT outperforms control (p = 0.001) and PBMT (p = 0.090) groups in healing. The findings indicate that aPDT and PBMT offer a promising approach to treating RHL.

Vaccination can prevent infections and modulate immune-related diseases. While conventional vaccines primarily stimulate CD4+ T cells and antibody production, effective anti-tumor immunity requires activation of CD8+ T cells. Photochemical internalization (PCI) is a promising technology that can facilitate cytosolic antigen delivery, promoting CD8+ T-cell responses. Here, we studied early immune and cutaneous reactions following PCI-based vaccination with the photosensitizer disulphonated tetraphenyl chlorine (TPCS2a). Mice were vaccinated intradermally with ovalbumin antigen and TPCS2a, followed by light treatment. We assessed cutaneous inflammatory reactions through histology, immunohistochemistry, fluorescence microscopy, and real-time PCR. Systemic inflammatory and immune reactions were analyzed in blood, lymph nodes, and in spleen by flow cytometry, clinical chemistry and ELISA. TPCS2a was retained in cutaneous structures, accumulated in draining lymph nodes, and light activation triggered dose- and time-dependent cutaneous inflammatory reactions including infiltration of innate myeloid CD11b+ and GR1+ macrophages, cross-presenting dendritic cells and neutrophils, alongside enhanced local and systemic production of pro-inflammatory cytokines. High TPCS2a doses triggered severe cutaneous and systemic reactions, but PCI-treated skin showed a high degree of plasticity and healing. These mechanistic insights into local and systemic effects of PCI-based vaccination may contribute to translating PCI into clinical practice and wider application.

Posterior capsular opacification (PCO) causes the vision that has been restored after cataract surgery to become blurred again. YAG laser treatment for PCO not only incurs additional costs but also poses risks of complications, including glaucoma and retinal disorders. Effective prevention and management of PCO remain an area requiring active research. Photodynamic therapy (PDT) utilizes a photosensitizer (PS) to transform oxygen into reactive oxygen species (ROS) under specific wavelengths of light, thereby inducing apoptosis. Given its minimal invasiveness and high specificity, PDT has been extensively applied in the treatment of conditions characterized by abnormal cell proliferation, such as tumors. Considering the pathogenesis of PCO, PDT has demonstrated promising clinical application potential in ophthalmic disease treatment. This review examines the impact of photodynamic therapy on the biological behavior of lens epithelial cells (LECs) and its efficacy in treating PCO. It also discusses the advantages and disadvantages of different photosensitizers and their clinical application potential.

Known as double primary cancers or duplicated cancers, are the simultaneous occurrence of two or more primary malignancies with different histological type. The location and stage of each tumor determine the degree of complexity of treatment. Conventional methods pose great difficulties since a single modality is usually inadequate to reach total eradication.

This paper addresses a 66-year-old male patient diagnosed with an esophageal tumor whose presence had been observed for more than one month without any particular symptoms or signs. The patient presented an unusual example of dual primary early carcinoma involving the cardia and the upper esophagus. Given single-modality techniques were insufficient for total eradication, the tumor in the upper esophagus, which was proximally to the neck, presented special difficulties for conventional treatment. We followed a thorough treatment schedule combining endoscopic photodynamic therapy with surgical resection. With no appreciable disease progression or complications noted over a 32-month follow-up period, this strategy produced good clinical results.

In this case, surgical intervention and photodynamic therapy worked well, providing new optionsfor treating similar clinical situations.

Photodynamic therapy (PDT) is widely utilized in cancer treatment as a noninvasive strategy. Phycocyanin (PC), a natural water-soluble photosensitizer with nontoxic properties, shows promise as a PDT candidate. However, the limitations of PC when used alone in PDT for cancer treatment, such as inadequate tumor delivery and weak efficacy, must be addressed. Herein, an efficient theranostic manganese (Mn)-based PC nanocomplex (PC@Mn) was synthesized through a straightforward one-pot self-assembly reaction for synergistic antitumor therapy. The PC@Mn nanoparticles were found to have a suitable size (∼129 nm) and demonstrated excellent biocompatibility and biosafety. Importantly, these nanoparticles exhibited enhanced biodistribution with improved tumor targeting and retention properties. When combined with 650 nm laser irradiation, PC@Mn showed a significant enhancement in the PDT effect in vivo. Additionally, PC@Mn displayed promising magnetic resonance (MR) imaging capabilities, with a high relaxation rate (r1 = 10.14 mM-1 s-1) and an extended imaging time window (4 h). This feature enables real-time monitoring of the nanoparticles' distribution within tumors, facilitating precise determination of the optimal PDT treatment time. Overall, the study highlights PC@Mn as a simple, safe, and highly efficient strategy for synergistic antitumor therapy. Its ability to combine PDT with MR imaging for real-time guidance represents an efficient approach to cancer treatment, promising improved therapeutic outcomes and potential clinical applications in the future.

Sonodynamic therapy (SDT) is a novel non-invasive treatment method that combines low-intensity ultrasound and sonosensitizers. Compared with photodynamic therapy, SDT has the advantages of deeper tissue penetration, higher accuracy and fewer adverse reactions. Sonosensitizers are essential for the efficacy of SDT. Sonosensitizers have the advantages of clear structure, easy monitoring, evaluation of drug metabolism and clinical transformation, etc. Notably, biochemical techniques can be used in the field of sonosensitizers and SDT to overcome inherent barriers and achieve sustainable innovation. This article first summarizes the molecular mechanism of SDT, focusing on organic sonosensitizers, inorganic nano-sonosensitizers and multi-functional drug delivery systems with targeting, penetration and imaging functions after a series of modifications. This review provides ideas and references for the design of sonosensitizers and SDT and promotes their future transformation into clinical applications.

Optical-quality bioresorbable implants, which gradually dissolve within the body, are gaining increasing interest due to their potential to eliminate the need for revision surgeries. These implants show significant promise in treating deep-seated tumors in high-risk areas, such as the brain, and offer extended capabilities for monitoring interstitial physiological parameters or pharmacokinetics through photonic technologies.

A proof-of-principle validation has been conducted on calcium phosphate glass (CPG)-based bioresorbable optical fibers to assess their capability to monitor the spatial distribution of photosensitizing (PS) drugs in tumors-an essential parameter to optimize for enhanced treatment outcomes in photodynamic therapy (PDT).

Ex vivo validation was performed on liquid phantoms with solid tumor-mimicking inclusions containing the fluorescent PS drug. In-house developed bioresorbable fibers, with optical characteristics similar to silica fibers used in current PDT systems, were utilized. For the first time, these fibers were used for the interstitial acquisition of fluorescent signals, followed by the tomographic reconstruction of the drug distribution in the phantom. The results were compared with those obtained from a standard clinical system equipped with silica fibers.

The reconstructed drug distribution with bioresorbable fibers agreed with that obtained using the same system with standard silica fibers.

We reveal the potential of further exploring CPG bioresorbable optical fibers for interstitial PDT.

Photodynamic therapy (PDT) remains underutilized as a primary cancer treatment due to the limited lethality of reactive oxygen species (ROS) and poor targeting efficiency of traditional photosensitizers. This the aim of the study is to develop a Fe₃O₄@ZnO nanoparticle photosensitizer co-loaded with anti-EGFR antibody, brusatol, and Nrf2-siRNA to improve the therapeutic effect of PDT. This system can be guided to tumors by a magnetic field and further targets cancer cells through EGFR-specific binding. Under UVA light, brusatol and Nrf2-siRNA are released, enabling combined chemo-, gene, and photodynamic therapy. With the photosensitizer treatment, ROS levels in cutaneous squamous cell carcinoma cells were elevated by 191.09 ± 10.02 % through suppression of Nrf2 and its associated antioxidant defenses, significantly enhancing cell lethality and reducing cell viability by 80.43 ± 9.37 %. In vivo studies further demonstrated a tumor suppression rate of 76.30 ± 5.12 % in nude mice, highlighting the robust anti-tumor efficacy of the photosensitizer and its potential for clinical application in targeted cancer therapy. The biocompatibility and high therapeutic efficacy of this photosensitizer highlight its promise as a safer and more effective option for treating cutaneous squamous cell carcinoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, originating from the melanocytes within the uvea. Currently, the treatment of ocular tumors predominantly relies on conventional approaches such as brachytherapy and enucleation. Despite the limited pharmaceutical treatment options for uveal melanoma (UM), the effectiveness of ocular drug delivery is hindered by the ocular barrier to local drug administration and the complex tumor microenvironment (TME). In response, biomimetic low-density lipoprotein nanoparticles (LD-DPVP NPs) with active targeting capabilities were designed. This nanodrug system combined photosensitizer (verteporfin, VP) with the tumor vascular normalization drug (dexamethasone, DEX) to achieve low-toxicity, high-efficacy treatment of intraocular tumors. After intravenous injection, the nanoparticles selectively targeted the tumor site and induced VP to produce reactive oxygen species (ROS) that killed tumor cells under near-infrared laser stimulation. The produced ROS could also trigger the cleavage of the DEX prodrug (DPD) and rapid release of DEX via breakage of the thioether bond (TK). Additionally, DEX could modulate the TME, improving the delivery of nanoparticles to the tumor and further enhancing the efficacy of LD-DPVP NPs. We believe the biomimetic nanoparticles designed in this study have a potential clinical application value in inhibiting UM growth and provided a promising strategy for addressing other ocular malignancies.

Antibody-drug conjugates (ADCs) represent a novel class of biopharmaceuticals comprising monoclonal antibodies covalently conjugated to cytotoxic agents via engineered chemical linkers. This combination enables targeted delivery of cytotoxic agents to tumor site through recognizing target antigens by antibody while minimizing off-target effects on healthy tissues. Clinically, ADCs overcome the limitations of traditional chemotherapy, which lacks target specificity, and enhance the therapeutic efficacy of monoclonal antibodies, providing higher efficacy and fewer toxicity anti-tumor biopharmaceuticals. ADCs have ushered in a new era of targeted cancer therapy, with 15 drugs currently approved for clinical use. Additionally, ADCs are being investigated as potential therapeutic candidates for autoimmune diseases, persistent bacterial infections, and other challenging indications. Despite their therapeutic benefits, the development and application of ADCs face significant challenges, including antibody immunogenicity, linker instability, and inadequate control over the release of cytotoxic agent. How can ADCs be designed to be safer and more efficient? What is the future development direction of ADCs? This review provides a comprehensive overview of ADCs, summarizing the structural and functional characteristics of the three core components, antibody, linker, and payload. Furthermore, we systematically assess the advancements and challenges associated with the 15 approved ADCs in cancer therapy, while also exploring the future directions and ongoing challenges. We hope that this work will provide valuable insights into the design and optimization of next-generation ADCs for wider clinical applications.

Angiosarcomas are sporadic vascular neoplasms among the most aggressive subtypes of soft tissue sarcomas. In addition, vast and multiple recurrent superficial scalp and facial angiosarcomas are very complex and extremely difficult to manage. Their occurrence brings about significant social and emotional distress to affected individuals. To date, no specific therapeutic strategy has been the most effective and reliable. Herein, we report a highly unique case of a geriatric male patient with recurrent scalp and facial angiosarcoma successfully treated by a chemotherapy-free regimen consisting of photodynamic therapy (PDT), immunotherapy, and target therapy. Notably, PDT provided promising remarkable auspicious outcomes and proved to be a better therapeutic option for refractory malignant angiosarcomas.

One of the most urgent threats to public health worldwide is the ongoing rise of multidrug-resistant (MDR) bacterial strains. Among the most critical pathogens are MDR-Klebsiella pneumoniae strains. The lack of new antibiotics has led to an increased need for non-antibiotic antimicrobial therapies. Photodynamic therapy (PDT) has become increasingly significant in treating MDR bacteria. PDT uses photosensitizer compounds (PS) that generate reactive oxygen species (ROS) when activated by light. These ROS produce localized oxidative stress, damaging the bacterial envelope. A downside of PDT is the limited bioavailability of PSs in vivo, which can be enhanced by conjugating them with carriers like nanoparticles (NPs). Zinc nanoparticles possess antibacterial properties, decreasing the adherence and viability of microorganisms on surfaces. The additive or synergistic effect of the combined NP-PS could improve phototherapeutic action. Therefore, this study evaluated the effectiveness of the copper(I)-based PS CuC1 compound in combination with Zinc Oxide NP, ZnONP, to inhibit the growth of both MDR and sensitive K. pneumoniae strains. The reduction in bacterial viability after exposure to a PS/NP mixture activated by 61.2 J/cm2 of blue light photodynamic treatment was assessed. The optimal PS/NP ratio was determined at 2 µg/mL of CuC1 combined with 64 µg/mL of ZnONP as the minimum effective concentration (MEC). The bacterial gene response aligned with a mechanism of photooxidative stress induced by the treatment, which damages the bacterial cell envelope. Additionally, we found that the PS/NP mixture is not harmful to mammalian cells, such as Hep-G2 and HEK-293. In conclusion, the CuC1/ZnONP combination could effectively aid in enhancing the antimicrobial treatment of infections caused by MDR bacteria.

Photodynamic therapy (PDT) represents a spatiotemporal and minimally invasive treatment for superficial diseases. Enhancing the delivery efficiency of photosensitizers and elevating oxygen levels at the lesion site are two established strategies for improving its effectiveness. Here, we introduce a strategy involving the release of pressurized oxygen to drive photosensitizer diffusion, which is incorporated into a core-shell microneedle (MN) system to improve PDT. This MN system comprises a polyvinylpyrrolidone shell and methylene blue (MB) photosensitizer loaded core particles containing pressurized oxygen bubbles. Upon insertion, the aqueous tissue environment triggers the dissolution of particles within the MNs, enabling the rapid release of oxygen, thereby promoting the diffusion of MB. In vitro experiments demonstrate that these particles could effectively accelerate the release and diffusion of MB. The released oxygen could relieve hypoxia and increase the generation of reactive oxygen species (ROS) of PDT. In a mouse melanoma model, the MN system enhances tumor growth inhibition induced by PDT and mitigates tumor metastasis. This innovative system offers an autonomous, safe, and convenient approach for localized gas delivery and drug diffusion, potentially creating new avenues for efficiently combining gas and other therapies for superficial diseases.

Biotin is primarily taken up by cells through sodium-dependent multivitamin transporter, which is highly expressed in aggressive cancer cell lines, often at levels surpassing those of the folate receptor. This makes biotin an attractive ligand for tumor-targeted drug delivery. Building on this rationale, this study presents a series of six D-(+)-biotin-conjugated squaraine dyes derived from benzothiazole, indolenine, and benz[e]indole, with N-ethyl and N-hexyl chains. These compounds were thoroughly characterized in terms of their photophysical and photochemical properties, revealing strong absorption in the so-called "phototherapeutic window", notable fluorescence, especially the benzothiazole derivatives, aqueous stability, particularly the indolenine-based dyes, and moderate to high photostability. Computational studies further indicated a strong binding affinity to human serum albumin and avidin proteins. All dyes exhibited photodynamic activity, with indolenine derivatives showing remarkable tumor selectivity and benz[e]indole analogs evidencing superior photocytotoxicity. The most promising compounds preferentially accumulated in mitochondria, and both singlet oxygen and other reactive oxygen species were found to play a role in their photobiological effects. Additionally, they were non-genotoxic in the absence of irradiation, and apoptosis was the primary mechanism of cell death upon light activation. This was evidenced by preserved cytoplasmic membrane integrity, nuclear fragmentation, and caspase-3/7 activation, reinforcing the safety and potential of these compounds as phototherapeutic agents. Although cellular uptake via the sodium-dependent multivitamin transporter was not established, and diffusion is expected to be the predominant mechanism, the high predicted avidin-binding affinity of these dyes opens exciting new avenues for photodynamic therapy-combined strategies.

Photodynamic therapy (PDT) represents a high-efficient and non-invasive therapeutic modality for current and future tumor treatments, drawing extensive attention in the fields of antitumor drug and clinical phototherapy. In recent years, the photosensitizer (PS) market and PDT clinical applications have expanded to address various cancers and skin diseases. However, hypoxic environment within tumors poses a substantial challenge to the therapeutic capability of reactive oxygen species-dependent PDT. Consequently, researches have increasingly focus from the type II to type I PDT mechanism, which relies on radical production with less or no oxygen dependence. Despite significant progress in the development of type I PSs, a holistic understanding regarding the design principles for these molecules remains elusive. Specifically, electron transfer-mediated type I PDT are extensively studied in recent years but is insufficiently addressed in existing reviews. This review systematically summarizes recent advancements in the molecular design rationales of organic type I PSs, categorizing them into three key fundamental strategies: modulating PS charge distribution, singlet oxygen forbidden via low triplet excited state, and accelerating PS radical formation via inducing electron transfer. This review aims to offer valuable insights for the future type I PS design and the advancement of anti-hypoxia PDT.

Background/Objectives: Primary cutaneous lymphomas (CLs) are a group of skin-limited lymphoproliferative disorders, including cutaneous T-cell (CTCLs) and B-cell lymphomas (CBCLs). Photodynamic therapy (PDT), a non-invasive, light-activated treatment, has gained attention as a skin-directed therapy for early-stage CLs due to its selectivity and favorable safety profile. This systematic review evaluates the current evidence on the clinical use of PDT in managing CLs. Methods: A systematic literature search was conducted in PubMed, Scopus, and Embase through 1 September 2024 following PRISMA guidelines. Search terms included "primary cutaneous skin lymphoma", "CTCL", "CBCL", "mycosis fungoides", "lymphomatoid papulosis", and "photodynamic therapy". After screening 1033 records, 30 studies were included. Data were extracted and categorized by lymphoma subtype and clinical outcomes. Results: Of the included studies, 23 focused on mycosis fungoides (MF), 5 on lymphomatoid papulosis (LyP), and 2 on CBCL. PDT demonstrated notable clinical efficacy in early-stage and localized disease, particularly MF, using methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA) as photosensitizers. Adjunctive techniques like microneedling and laser-assisted delivery improved treatment outcomes. PDT was generally well tolerated, with mild, transient side effects; rare complications such as localized neuropathy were reported. Conclusions: PDT is a promising, non-invasive treatment for early-stage CLs, especially MF and indolent CBCL variants. While current evidence supports its safety and effectiveness, further comparative and prospective studies are needed to refine protocols, evaluate long-term efficacy, and compare different photosensitizers.

Cancer, being one of the most outrageous diseases, contributed to 48 % of the mortality in 2022, with lung cancer leading the race with a 12.4 % incidence rate. Conventional treatment modalities like radio-, chemo-, photo-, and immunotherapy employing nanocarriers often face several setbacks, such as non-specific delivery, off-site toxicity, rapid opsonization via the host immune system, and greater tumor recurrence rates. Moreover, the heterogeneous variability in the tumor microenvironment is responsible for existing therapy failure. With the advent of biomimetic nanoparticles as a novel and intriguing platform, researchers have exploited the inherent functionalities of the Cluster of Differentiation proteins (CD) as cell surface biomarkers and imparted the nanocarriers with enhanced homologous tumor targetability, immune evasion capability, and stealth properties, paving the way for improved therapy and diagnosis. This article explores pathogenesis and the multifaceted role of immune cells in non-small cell lung cancer. Moreover, the agenda of this article is to shed light on biomimetic nanoarchitectonics with respect to their fabrication, evaluation, and applications unraveling their synergistic effect with conventional therapies. Further discussion mentions the hurdles in clinical translation with viable solutions. The regulatory bottlenecks underscore the need for a regulatory roadmap with respect to commercialization. We believe that biomimetic nanoarchitectonics will be a beacon of hope in warfare against lung cancer.

The biomedical applications of BODIPY fluorophores are limited by challenges such as short-wavelength emission, high hydrophobicity, and poor selectivity. To address these issues, two water-soluble red-emitting BODIPY derivatives, namely, PSPyBDP and I-PSPyBDP, were synthesized by conjugating pyridine units to the BODIPY core, followed by the ring-opening reactions with 1,3-propanesulfonate. Notably, PSPyBDP showed fast mitochondrial imaging capability (∼5 min), indicating its potential as an alternative to mitochondria tracker. I-PSPyBDP, with the heavy-atom effect, could effectively produce singlet oxygen (1O2) under irradiation at 660 nm in a short time (∼1 min) with a 1O2 quantum yield of 0.89. Cytotoxicity assays revealed that the BODIPY derivatives exhibited phototoxicity to HeLa cells while maintaining low dark toxicity. Interestingly, they had low toxicity against normal COS-7 cells. Confocal imaging and flow cytometry confirmed that the BODIPY derivatives could increase intracellular reactive oxygen species (ROS), reduce mitochondrial membrane potential, and induce apoptosis upon irradiation. These findings suggest their promising application in photodynamic therapy (PDT) for tumors.

Low-temperature second near-infrared region (NIR-II) photothermal therapy (PTT) has shown significant potential in minimizing damage to normal tissues and reducing inflammation. However, it still faces challenge of insufficient immune response. Thus, a multifunctional phototheranostic nanoparticle (BDPB/Pt/Fe@P[5]) is developed by co-loading BDPB, CDHPt, and Fe2⁺ with a pH-sensitive lipid DSPE-PEOz2K. The carboxylatopillar[5]arene (CP[5]) used to construct this nanoparticle exhibits strong host-guest recognition with pyridine salts, alleviating aggregation caused quench (ACQ) effect and enhancing the NIR-II emission of the donor-acceptor-donor (D-A-D)-type organic small molecule (BDPB). CP[5] provides suitable vehicles for encapsulating platinum (IV) prodrugs (CDHPt) and Fe2⁺ ions via metal coordination for controllable reactive oxygen species (ROS) release. Under low-intensity NIR-II laser irradiation and an acidic tumor microenvironment, the nanoparticles degrade, releasing CDHPt and Fe2⁺ ions for platinum-based therapy and chemodynamic therapy (CDT). CDHPt facilitates the direct production of superoxide anions (O₂·⁻) from O₂ and partially converts it into the highly cytotoxic hydroxyl radicals, thereby promoting the Fenton reaction process. The therapeutic efficacy is further synergized by immunogenic cell death (ICD) effect.

Skin cancer is a common malignant tumor that poses significant global health and economic burdens. The main clinical types include malignant melanoma and non-melanoma. Complications such as post-surgical recurrence, wound formation, or disfigurement can severely impact the patient's mental well-being. Traditional treatments such as surgery, chemotherapy, radiation therapy, and immunotherapy often face limitations. These challenges not only reduce the effectiveness of treatments but also negatively impact patients' quality of life. Phototherapy, a widely used and long-standing method in dermatology, presents a promising alternative for skin cancer treatment. Light-triggered nanomaterials further enhance the potential of phototherapy by offering advantages such as improved therapeutic precision, controlled drug release, minimal invasiveness, and reduced damage to surrounding healthy tissues. This review summarizes the application of light-triggered nanomaterials in skin cancer treatment, focusing on the principles, advantages, and design strategies of photodynamic therapy (PDT), photothermal therapy (PTT), and photoacoustic therapy (PAT). In this manuscript we have an in-depth discussion on overcoming translational barriers, including strategies to enhance light penetration, mitigate toxicity, reduce production costs, and optimize delivery systems. Additionally, we discuss the challenges associated with their clinical translation, including limited light penetration in deep tissues, potential toxicity, high production costs, and the need for advanced delivery systems.

Due to limited light penetration and dependence on oxygen, photodynamic therapy (PDT) is typically restricted to treating shallow tissues. Developing strategies to overcome these limitations and effectively using PDT for tumor treatment is a significant yet unresolved challenge. In this study, we present a smart approach combining a wireless-charged LED (wLED) with a type I aggregation-induced emission photosensitizer, MeOTTMN, to address both light penetration and tumor hypoxia issues simultaneously. MeOTTMN, characterized by twisted molecular architecture and strong intramolecular electron donor-acceptor interaction, produces high levels of hydroxyl and superoxide radicals and emits near-infrared light in its aggregated state, thus facilitating fluorescence imaging-guided PDT once formulated into nanoparticles. The inhibition of breast cancer xenografts provides compelling evidence of the treatment efficacy of type I PDT irradiated through an implantable wLED. This strategy provides a conceptual and practical paradigm to overcome key clinical limitations of PDT, expanding possibilities for clinical translation.

Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine. Here, we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs) as a bimodal system for image-guided phototherapy in bladder cancer treatment. PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation, but also exhibit potent autophagy blockage, effectively inducing bladder cancer cell death. Furthermore, PPBC LNPs possess remarkable photoacoustic (PA) and fluorescence (FL) imaging capabilities, enabling imaging with high-resolution, deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy. Specifically, PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy, while FL imaging confirms their prolonged retention at the tumor site for up to 6 days. PPBC LNPs significantly suppress bladder tumor growth, with several tumors completely ablated following just two doses of the nanoparticles and laser treatment. Additionally, PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility, stability, and scalability, showing potential for clinical translation. This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.

In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.

Reactive oxygen species (ROS) play a double-edged role in gastric cancer (GC). Higher levels of ROS in tumor cells compared to normal cells facilitate tumor progression. Once ROS concentrations rise rapidly to toxic levels, they cause GC cell death, which is instead beneficial for GC treatment. Based on these functions, nano-delivery systems taking the therapeutic advantages of ROS have been widely employed in tumor therapy in recent years, overcoming the drawbacks of conventional drug delivery techniques, such as non-specific systemic effects. In this review, the precise impacts of ROS on GC have been detailed, along with ROS-based nanomedicine therapeutic schemes. These strategies mainly focused on the use of excess ROS in the tumor microenvironment for controlled drug release and a substantial enhancement of ROS concentrations for tumor killing. The challenges and opportunities for the advancement of these anticancer therapies are also emphasized.

Hypericin, also known as naphthodianthrone, is a naturally occurring photosensitiser derived from anthraquinone. It has gained attention owing to its prospective use in photodynamic therapy (PDT) for cancer treatment. PDT is a minimally invasive treatment that utilises light, a photosensitiser, and oxygen to kill the target cells. However, conventional synthesis methods of hypericin harm the environment and human health. Therefore, researchers focused on developing green extraction methods for hypericin to overcome these limitations. In this study, hypericin was extracted from Hypericum perforatum using a green -synthesis method and characterised using Fourier-transform infra-red spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV), high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC). Hypericin generates reactive oxygen species (ROS) upon light activation, which disrupts bacterial cell walls and inhibits vital metabolic processes. This mechanism ensures potent antibacterial effects against both gram-positive S. aureus and gram-negative E. coli, making hypericin a prominent photosensitiser for photodynamic antibacterial therapy.

The incidence of melanoma, the third most common skin cancer, has been on the rise in recent years. In addition, it has a high mortality rate due to its high aggressiveness. Phototherapy, as a promising treatment method, can effectively kill tumor cells, but it is incapable of the treatment of tumor metastasis. Herein, a nanomaterial (TPC@OVA NPs) is developed for phototherapy in conjunction with immunotherapy against melanoma. TPC, as a derivative of porphyrin, is used as a photosensitizer with excellent biosafety and photostability. After assembly with ovalbumin (OVA), TPC@OVA NPs with vaccine properties is formed, which can not only ablate the primary tumor but also induce immunogenic cell death (ICD). In addition, DC cells can be stimulated to mature by exogenous OVA, enhancing the immune response against tumors by further activating T lymphocytes. Combined with immune checkpoint inhibitor aPD-1, the immune microenvironment is reshaped, and the increased activity of immunotherapy are validated. This work highlights the potential of combining phototherapy and immunotherapy against metastasis.