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Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔE S-T ) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. STATEMENT OF SIGNIFICANCE: (1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT); (2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells; (3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In this work, various novel pyridinyl- and pyridinium-modified Aza-BODIPY PSs were designed and constructed based on monoiodo Aza-BODIPY PSs ( BDP-4 and BDP-15 ) in an attempt to construct "structure-inherent organelles-targeted" PSs to endow potential organelle-targeting ability. Pyridinyl PSs displayed potent photodynamic efficacy, and monorigidified PSs were very effective. The monorigidified PS 20 with meta -pyridinyl moiety displayed the most potent photoactivity and negligible dark toxicity with a favorable dark/phototoxicity ratio (>4800). To our surprise, monorigidified PS with meta -pyridinyl moiety (e.g., 20 ) was lipid droplet-targeted. 20 showed good cellular uptake and intracellular ROS generation compared with BDP-15 . The preliminary cell death process exploration indicated that 20 resulted in lipid peroxidation and induced cell death through an iron-independent ferroptosis-like cell death pathway. In vivo antitumor efficacy experiments manifested that 20 significantly inhibited tumor growth and outperformed BDP-15 and Ce6 even under a single low-dose light irradiation (30 J/cm 2 ).

Darier disease and Hailey-Hailey disease are rare autosomal dominant genodermatoses that negatively impact patient quality of life. In addition, they pose challenges to dermatologists who manage these diseases. There is currently no treatment that reliably induces remission for either disease, leaving patients dependent on symptom management. Oral and topical retinoids are the most commonly used therapies but have numerous side effects that often lead to discontinuation or inability to tolerate long-term treatment (Burge and Wilkinson in J Am Acad Dermatol 27:40-50, 1992). Due to the rarity of these diseases, there are no clinical trials investigating treatment options for the persistent flares patients experience. In light of this, dermatologists have tried various methods used in the management of other inflammatory disorders including photodynamic therapy (PDT). A systematic review was conducted to investigate this treatment option which yielded a total of 12 studies that had reported the use of photodynamic therapy (PDT) as a treatment option for Darier or Hailey-Hailey disease. Though results showed that PDT can induce disease remission for up to several months or years, there are many unanswered questions that need to be addressed before adopting PDT as a leading treatment option for those genodermatoses. In particular, cost, tolerability, and efficacy and safety in patients who are skin of color need to be further studied. Lastly, recommendations on treatment duration, number of sessions, photosensitizing agents, lasers, and continuation or discontinuation of topical and systemic medications need to be appraised before formal recommendations can be made., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Photodynamic therapy (PDT) has recently come to the forefront as an exceptionally powerful and promising method for the treatment of cancer. Existing photosensitizers are predominantly engineered to target diverse biomolecules, including proteins, DNA, lipids, and carbohydrates, and have proven to greatly enhance the efficacy or specificity of PDT. However, it is noteworthy that there exists a conspicuous scarcity of photosensitizers specifically designed to target RNAs. Recognizing the crucial and multifaceted roles played by RNAs in various cellular processes and disease states, we have ventured into the development of a novel RNA-targeting photosensitizer, named Se-718 , designed specifically for PDT-based cancer therapy. Se-718 has been engineered to exhibit a high molar absorption coefficient in the NIR region, which is crucial for effective PDT. More importantly, Se-718 has demonstrated a distinct RNA-targeting capability, as evidenced through rigorous testing in both circular dichroism and fluorescence experiments. Furthermore, Se-718 has been shown to display both type I and type II photodynamic properties. This unique characteristic enables the efficient killing of cancer cells under a wide range of oxygen conditions, both normoxic (21% O 2 ) and hypoxic (2% O 2 ). The IC 50 of Se-718 can be as low as 100 nM, and its light-to-dark toxicity ratio is an impressive 215 times higher, outperforming most photosensitizers currently available. Moreover, in vivo studies conducted with tumor-bearing mice have demonstrated the excellent antitumor effects and high safety profile of Se-718 . Considering the outstanding PDT efficacy of Se-718 , we are optimistic that the development of RNA-targeting photosensitizers may provide an innovative and highly effective option for cancer therapeutics in the near future.

Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3-bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL-mediated PDT inhibited tumor growth by >90 % with 40 % of mice being tumor-free, rejected tumor re-challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98 % tumor inhibition and 80 % of mice being tumor-free., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO 2 , IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment., (© 2024. The Author(s).)

Objective: To assess the effectiveness of antimicrobial photodynamic therapy (aPDT) employing an annatto-based (20%) dye combined with blue LED for the treatment of halitosis in mouth-breathing children., Materials and Methods: Fifty-two children six to twelve years of age with diagnoses of mouth breathing and halitosis (score of ≥ 3 on portable breath meter) Breath Alert™ (Tanita Corporation®-Japan), were randomly allocated to two groups (n = 26). Group 1: brushing, dental floss and aPDT applied to middle third of the dorsum of the tongue. Group 2: brushing, dental floss and tongue scraper. Breath meter results before, immediately after treatment as well as seven and 30 days after treatment were compared. The hypothesis of normality in the data was discarded by the Shapiro-Wilk test (p < 0.05) and for statistical analysis the Wilcoxon and Mann-Whitney tests were used., Results: A significant difference was found between the pre-treatment reading and all other readings (p < 0.05) in both groups, suggesting the effectiveness of the proposed treatments. No significant difference was found between the post-treatment reading and two follow-up readings, suggesting the maintenance of the effect of treatment over time (p > 0.05). However, significant differences were found between groups for all post-treatment assessments (p < 0.0001 for all comparisons), indicating greater effectiveness with aPDT. No association was found between the initial reading and the presence of coated tongue., Conclusion: Antimicrobial photodynamic therapy using annatto and blue LED proved to be a viable therapeutic option for the treatment of halitosis in mouth-breathing children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bruno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

ConspectusDue to the advantages of spatiotemporal selectivity and inherent noninvasiveness, cancer phototherapy, which includes both photodynamic therapy (PDT) and photothermal therapy (PTT), has garnered significant attention in recent years as a promising cancer treatment. Despite the commendable progress in this field, persistent challenges remain. In PDT, limitations in dyes manifest as low intersystem crossing (ISC) efficiency and oxygen-dependent photoactivity, resulting in unsatisfactory performance, particularly under hypoxic conditions. Similarly, PTT encounters consistent insufficiencies in the photothermal conversion efficiency (PCE) of dyes. Additionally, the suboptimal phototherapeutic efficacy often exhibits a limited immune response. These factors collectively impose significant constraints on phototherapy in oncological applications, leading to limited tumor inhibition, tumor recurrence, and even metastasis.Unlike strategies that rely on external assistance with complicated systems, manipulating excited-state deactivation pathways in biocompatible dyes offers a universal way to systematically address these challenges. Our group has devoted considerable effort to achieving this goal. In this Account, we present and discuss our journey in optimizing excited-state energy-release pathways through regulating molecular charge transfer based on cyanine dyes, which are renowned for their exceptional photophysical properties and harmonious biocompatibility. The investigation begins with the introduction of amino groups in the meso position of a heptamethine cyanine dye, where the intramolecular charge transfer (ICT) effect causes a significant enlargement of the Stokes shift. Subsequently, ICT induced by introducing functional electron-deficient groups in cyanines is found to decrease the overlap of electron distribution or narrow the energy gaps of molecular frontier orbitals. Such modifications result in a reduction of the energy gaps between singlet and triplet states or an improvement in internal conversion, ultimately promoting phototherapy efficacy in both primary and distant tumors. Furthermore, with the intensification of the charge transfer effect aided by light, photoinduced intramolecular electron transfer occurs in some cyanines, leading to complete charge separation in the excited state. This process enhances the transition to the ground or triplet states, improving tumor phototherapy and inhibiting metastasis by increasing the PCE or the yield of reactive oxygen species, respectively. Shifting focus from intramolecular to intermolecular interactions, we successfully constructed and explored cyanines based on intermolecular charge transfer. These dyes, with excited-state dynamics mimicking natural photosynthesis, generate radicals and facilitate oxygen-independent hypoxic tumor PDT. Finally, we outlined the existing challenges and future directions for optimizing phototherapeutic efficacy by regulating molecular charge transfer. This Account provides molecular-level insights into improving phototherapeutic performance, offering valuable perspectives, and inspiring the development of functional dyes in other application fields.

Purpose: To compare haze and refractive outcomes in patients undergoing combined accelerated corneal cross-linking (A-CXL) and selective wavefront-guided transepithelial photorefractive keratectomy (WG-transPRK) without mitomycin C (MMC) versus those undergoing A-CXL., Methods: This prospective study analyzed 95 eyes (86 patients) with progressive keratoconus from October 2018 to October 2022. The first group underwent CXL combined with corneal or ocular WG-transPRK (CXL+PRK, n = 52), targeting higher order aberrations (HOAs). The second underwent CXL only (n = 43), both following the same accelerated CXL protocol without MMC on the SCHWIND Amaris laser platform (SCHWIND eye-tech-solutions). Baseline and postoperative evaluations (1, 3, 6, and 12 months) included uncorrected (UDVA) and corrected (CDVA) distance visual acuity, manifest refraction, tomography, corneal HOAs, and optical coherence tomography (OCT) scans. A patented machine learning algorithm objectively detected and quantified stromal haze on OCT scans in grayscale units., Results: In both groups, anterior corneal haze reflectivity and subepithelial haze peaked at 3 months postoperatively, then progressively decreased at 6 and 12 months. Haze did not differ between groups at any time point. By 12 months, CDVA increased by 2.5 lines in the CXL+PRK group ( P < .001) and by 0.7 lines in the CXL group ( P = .10), and maximum keratometry decreased from 51.70 ± 5.10 to 47.90 ± 7.90 diopters (D) (CXL+PRK group) ( P < .001) and from 51.20 ± 5.10 to 50.30 ± 4.60 D (CXL group) ( P = .004). Corneal HOAs decreased in both groups but more in the CXL+PRK group., Conclusions: Combining CXL with WG-transPRK without MMC does not result in increased haze when compared to A-CXL alone. This combined approach achieves greater improvements in visual, topographic, and aberrometric parameters. [ J Refract Surg . 2024;40(9):e583-e594.] .

Objectives: To evaluate the 10-year visual, refractive, and tomographic outcomes of epithelium-off accelerated corneal collagen cross-linking (ACCL) in paediatric patients with progressive keratoconus (KC) and to compare the stages in terms of re-progression., Methods: Patients under 18 years of age with progressive KC who underwent ACCL between 2010 and 2012 and completed at least 10 years of follow-up were included in this retrospective study. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive errors, and corneal tomography parameters were evaluated preoperatively and at 1, 5, and 10 years postoperatively. The effect of stage and age on re-progression was analysed., Results: The study included 175 eyes of 97 patients (mean age: 14.46 ± 2.17 years). Improvement in UDVA and CDVA was observed in all postoperative periods compared to the preoperative period (each p-value < 0.05). The increase in spherical equivalent (SE), flattening of keratometry values, and decrease in thinnest corneal thickness (TCT) were statistically significant in the tenth year compared to preoperatively (each p-value < 0.05). Re-progression was observed in 16 eyes (9.14%). Haze was observed in 13 eyes (7.43%), 4 of which were permanent. Deep anterior lamellar keratoplasty was performed in 3 eyes (1.7%) and a second ACCL in 3 eyes (1.7%)., Conclusions: ACCL is an effective and safe long-term strategy to prevent progression of KC in paediatric patients. In the light of this study with a 10-year follow-up re-progression rate of 9.14%, long-term follow-up of patients after ACCL for possible re-progression and the need for re-CCL or keratoplasty may be recommended., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Photodynamic therapy (PDT) is a medical radio chemotherapeutic method that uses light, photosensitizing agents, and oxygen to produce cytotoxic compounds, which eliminate malignant cells. Recently, Microfluidic systems have been used to analyse photosensitizers (PSs) due to their potential to replicate in vivo environments. While prior studies have established a strong correlation between reacted singlet oxygen concentration and PDT-induced cellular death, the effects that the ambient fluid flow might have on the concentration of oxygen and PS have been disregarded in many, which limits the reliability of the results. Herein, we coupled the transport of oxygen and PS throughout the ambient medium and within the spheroidal multicellular aggregate to initially study the profiles of oxygen and PS concentration alongside PDT-induced cellular death throughout the spheroid before and after radiation. The attained results indicate that the PDT-induced cellular death initiates on the surface of the spheroids and subsequently spreads to the neighbouring regions, which is in great accordance with experimental results. Afterward, the effects that drug-light interval (DLI), fluence rate, PS composition, microchannel height, and inlet flow rate have on the therapeutic outcomes are studied. The findings show that adequate DLI is critical to ensure uniform distribution of PS throughout the medium, and a value of 5 h was found to be sufficient. The composition of PS is critical, as ALA-PpIX induces earlier cell death but accelerates oxygen consumption, especially in the outer layers, depriving the inner layers of oxygen necessary for PDT, which in turn disrupts and prolongs the exposure time compared to mTHPC and Photofrin. Despite the fluence rate directly influencing the singlet oxygen generation rate, increasing the fluence rate by 189 mW/cm 2 would not significantly benefit us. Microwell height and inlet flow rate involve competing phenomena-increasing height or decreasing flow reduces oxygen supply and increases PS "washout" and its concentration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Staphylococcus aureus is characterized by its high resistance to conventional antibiotics, particularly methicillin-resistant (MRSA) strains, making it a predominant pathogen in acute and chronic wound infections. The persistence of acute S. aureus wound infections poses a threat by increasing the incidence of their chronicity. This study investigated the potential of photodynamic activation using phytochemical-antibiotic combinations to eliminate S. aureus under conditions representative of acute wound infections, aiming to mitigate the risk of chronicity. The strategy applied takes advantage of the promising antibacterial and photosensitising properties of phytochemicals, and their ability to act as antibiotic adjuvants. The antibacterial activity of selected phytochemicals (berberine, curcumin, farnesol, gallic acid, and quercetin; 6.25-1000 μg/mL) and antibiotics (ciprofloxacin, tetracycline, fusidic acid, oxacillin, gentamicin, mupirocin, methicillin, and tobramycin; 0.0625-1024 μg/mL) was screened individually and in combination against two S. aureus clinical strains (methicillin-resistant and -susceptible-MRSA and MSSA). The photodynamic activity of the phytochemicals was assessed using a light-emitting diode (LED) system with blue (420 nm) or UV-A (365 nm) variants, at 30 mW/cm 2 (light doses of 9, 18, 27 J/cm 2 ) and 5.5 mW/cm 2 (light doses of 1.5, 3.3 and 5.0 J/cm 2 ), respectively. Notably, all phytochemicals restored antibiotic activity, with 9 and 13 combinations exhibiting potentiating effects on MSSA and MRSA, respectively. Photodynamic activation with blue light (420 nm) resulted in an 8- to 80-fold reduction in the bactericidal concentration of berberine against MSSA and MRSA, while curcumin caused 80-fold reduction for both strains at the light dose of 18 J/cm 2 . Berberine and curcumin-antibiotic combinations when subjected to photodynamic activation (420 nm light, 10 min, 18 J/cm 2 ) reduced S. aureus culturability by ≈9 log CFU/mL. These combinations lowered the bactericidal concentration of antibiotics, achieving a 2048-fold reduction for gentamicin and 512-fold reduction for tobramycin. Overall, the dual approach involving antimicrobial photodynamic inactivation and selected phytochemical-antibiotic combinations demonstrated a synergistic effect, drastically reducing the culturability of S. aureus and restoring the activity of gentamicin and tobramycin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Photodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO - ) is a type of inflammatory cytokine. The abnormal increase of ClO - in tumor cells is related to tumor pathogenesis and may be a "friend" for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task., Results: An acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO - responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO - with fluorescence "turn on" performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO - was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO - response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs., Significance and Novelty: A win-win integration strategy was proposed to design a tumor intracellular ClO - responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Phototherapy has garnered significant attention in the past decade. Photothermal and photodynamic synergistic therapy combined with NIR fluorescence imaging has been one of the most attractive treatment options because of the deep tissue penetration, high selectivity and excellent therapeutic effect. Benefiting from the superb photometrics and ease of modification, perylene diimide (PDI) and its derivatives have been employed as sensing probes and therapeutic agents in the biological and biomedical research fields, and exhibiting excellent potential. Herein, we reported the development of a novel organic small-molecule phototherapeutic agent, PDI-TN. The absorption of PDI-TN extends into the NIR region, which provides feasibility for NIR phototherapy. PDI-TN overcomes the traditional Aggregation-Caused Quenching (ACQ) effect and exhibits typical characteristics of Aggregation-Induced Emission (AIE). Subsequently, PDI-TN NPs were obtained by using an amphiphilic triblock copolymer F127 to encapsulate PDI-TN. Interestingly, the PDI-TN NPs not only exhibit satisfactory photothermal effects, but also can generate O 2 •- and 1 O 2 through type I and type II pathways, respectively. Additionally, the PDI-TN NPs emit strong fluorescence in the NIR-II region, and show outstanding therapeutic potential for in vivo NIR-II fluorescence imaging. To our knowledge, PDI-TN is the first PDI derivative used for NIR-II fluorescence imaging-guided photodynamic and photothermal synergistic therapy, which suggests excellent potential for future biological/biomedical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

5-Aminolevulinic acid (5-ALA) is a prodrug of porphyrin IX (PpIX). Disadvantages of 5-ALA include poor stability, rapid elimination, poor bioavailability, and weak cell penetration, which greatly reduce the clinical effect of 5-ALA based photodynamic therapy (PDT). Presently, a novel targeting nanosystem was constructed using gold nanoparticles (AuNPs) as carriers loaded with a CSNIDARAC (CC9)-targeting peptide and 5-ALA via Au-sulphur and ionic bonds, respectively, and then wrapped in polylactic glycolic acid (PLGA) NPs via self-assembly to improve the antitumor effects and reduce the side effect. The successful preparation of ALA/CC9@ AuNPs-PLGA NPs was verified using ultraviolet-visible, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The analyses revealed good sphericity with a particle size of approximately140 nm, Zeta potential of 10.11 mV, and slow-controlled release characteristic in a weak acid environment. Confocal microscopy revealed targeting of NCL-H460 cells by NPs by actively internalising CC9 and avoiding the phagocytic action of RAW264.7 cells, and live fluorescence imaging revealed targeting of tumours in tumour-bearing mice. Compared to free 5-ALA, the nanosystem displayed amplified anticancer activity by increasing production of PpIX and reactive oxygen species to induce mitochondrial pathway apoptosis. Antitumor efficacy was consistently observed in three-dimensionally cultured cells as the loss of integrity of tumour balls. More potent anti-tumour efficacy was demonstrated in xenograft tumour models by decreased growth rate and increased tumour apoptosis. Histological analysis showed that this system was not toxic, with lowered liver toxicity of 5-ALA. Thus, ALA/CC9@AuNPs-PLGA NPs deliver 5-ALA via a carrier cascade, with excellent effects on tumour accumulation and PDT through passive enhanced permeability and retention action and active targeting. This innovative strategy for cancer therapy requires more clinical trials before being implemented., Competing Interests: Declaration of competing interest The authors declare that they have no know competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O 2 to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Financial disclosures/conflicts of interest: The authors have no funding or conflicts of interest to disclose.

The stiffening effect of corneal crosslinking (CXL) treatment, a therapeutic approach for managing the progression of keratoconus, has been primarily investigated using uniaxial tensile experiments. However, this testing technique has several drawbacks and is unable to measure the mechanical response of cornea under a multiaxial loading state. In this work, we used biaxial mechanical testing method to characterize biomechanical properties of porcine cornea before and after CXL treatment. We also investigated the influence of preconditioning on measured properties and used TEM images to determine microstructural characteristics of the extracellular matrix. The conventional method of CXL treatment was used for crosslinking the porcine cornea. The biaxial experiments were done by an ElectroForce TestBench system at a stretch ratio of 1:1 and a displacement rate of 2 mm/min with and without preconditioning. The experimental measurements showed no significant difference in the mechanical properties of porcine cornea along the nasal temporal (NT) and superior inferior (SI) direction. Furthermore, the CXL therapy significantly enhanced the mechanical properties along both directions without creating anisotropic response. The samples tested with preconditioning showed significantly stiffer response than those tested without preconditioning. The TEM images showed that the CXL therapy did not increase the diameter of collagen fibers but significantly decreased their interfibrillar spacing, consistent with the mechanical property improvement of CXL treated samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Changes in the biomechanical and biochemical properties of the human cornea play an important role in the pathogenesis of ectatic diseases. A number of conditions in primarily acquired (keratoconus or pellucid marginal degeneration) or secondarily induced (iatrogenic keratectasia after refractive laser surgeries) ectatic disorders lead to decreased biomechanical stability. Corneal collagen cross-linking (CXL) represents a technique to slow or even halt the progression of ectatic pathologies. In this procedure, riboflavin is applied in combination with ultraviolet A radiation. This interaction induces the production of reactive oxygen species, which leads to the formation of additional covalent bonds between collagen molecules and subsequent biomechanical corneal strengthening. This procedure is so far the only method that partially interferes etiopathogenetically in the treatment of ectatic diseases that slows or stops the process of corneal destabilization, otherwise leading to the need for corneal transplantation. Besides, CXL process increases markedly resistance of collagenous matrix against digesting enzymes supporting its use in the treatment of corneal ulcers. Since the discovery of this therapeutic procedure and the first laboratory experiments, which confirmed the validity of this method, and the first clinical studies that proved the effectiveness and safety of the technique, it has been spread and adopted worldwide, even with further modifications. Making use of the Bunsen-Roscoe photochemical law it was possible to shorten the duration of this procedure in accelerated CXL and thus improve the clinical workflow and patient compliance while maintaining the efficacy and safety of the procedure. The indication spectrum of CXL can be further expanded by combining it with other vision-enhancing procedures such as individualized topographically-guided excimer ablation. Complementing both techniques will allow a patient with a biomechanically stable cornea to regularize it and improve visual acuity without the need for tissue transplantation, leading to a long-term improvement in quality of life., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The purpose of this review was to summarize the different surgical approaches combining photorefractive keratectomy (PRK) and corneal crosslinking (CXL), present each protocol template in a simple format, and provide an overview of the primary outcomes and adverse events., Methods: A literature review was conducted as outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eight different databases were searched. Papers were included if PRK was immediately followed by CXL., Results: Thirty-seven papers met the inclusion criteria of a total yield of 823. The latest research into simultaneous PRK and CXL has been shown to not only stabilize the cornea and prevent keratoconus progression but also improve the visual acuity of the patient. Improvements in uncorrected distance visual acuity and (spectacle) corrected distance visual acuity were found to be significant when considering all protocols. There were also significant reductions in K1, K2, mean K, Kmax, sphere, cylinder, and spherical equivalent. Random-effects analysis confirmed these trends. Corrected distance visual acuity was found to improve by an average of 0.18 ± 1.49 logMAR (Cohen's D [CD] 0.12; P <0.02). There was also a significant reduction of 2.57 ± 0.45 D (CD 5.74; P <0.001) in Kmax. Cylinder and spherical equivalent were also reduced by 1.36 ± 0.26 D (CD 5.25; P <0.001) and 2.61 ± 0.38 D (CD 6.73; P <0.001), respectively., Conclusions: Combining the 2 procedures appears to be of net benefit, showing stabilization and improvement of ectatic disease, while also providing modest gains in visual acuity. Since customized PRK and CXL approaches appear superior, a combination of these would likely be best for patients., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Nuclear and radiological accidents can occur due to poor management, in transportation, radiation therapy and nuclear wards in hospitals, leading to extreme radiation exposure and serious consequences for human health. Additionally, in many of previous radiological accidents, skin damage was observed in patients and survivors due to the high radiation exposure. However, as part of a medical countermeasures in a nuclear/radiological emergency, it is critical to plan for the treatment of radiation-induced skin damage. Hence, the new, non-invasive technology of photodynamic therapy (PDT) is projected to be more effectively used for treating skin damage caused by high-dose radiation. PDT plays an important role in treating, repairing skin damage and promoting wound healing as evidenced by research. This review, highlighted and recommended potential impacts of PDT to repair and decrease radiation-induced skin tissue damage. Moreover, we have suggested some photosensitizer (PS) agent as radio-mitigator drugs to decrease radiobiological effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate corneal biomechanical changes after corneal cross-linking (CXL) treatments with rose bengal-green light (RB-CXL) and riboflavin-UVA (RF-CXL)., Methods: A total of 60 freshly enucleated lamb eyes were obtained for this experimental study. Fifteen eyes were treated with RB-CXL using 0.1% RB solution (Group 1), 15 eyes were treated with RB-CXL using 0.2% RB solution (Group 2), 15 eyes were treated with RF-CXL using 0.1% RF solution (Group 3), and 15 eyes were used as controls (Group 4). The same treatment protocol (10-minute irradiation using a total of 5.4 J/cm 2 energy) was applied to all treatment groups. To evaluate corneal biomechanical changes, the stress-strain test was used for both the treated and control corneas. The elastic modulus was calculated using the tension strain curves obtained during the test., Results: The average elastic modulus values were calculated to be 18.9, 23.5, 22.3, and 14.1 MPa in Groups 1, 2, 3, and 4, respectively. Statistically significant differences were found between the groups ( p  < 0.001 for Group 1 vs. 2; p  < 0.001 for Group 1 vs. 3; p  < 0.001 for Group 1 vs. 4; p  = 0.002 for Group 2 vs. 3; p  < 0.001 for Group 2 vs. 4; and p  < 0.001 for Group 3 vs. 4)., Conclusions: In this study, the efficacy of RB-CXL treatment applied using different concentrations of RB solutions at a total energy of 5.4 J/cm 2 was investigated, and 0.2% RB solution was found to have at least as much and even more effective than the RF-CXL (0.1% RF) on the corneal elasticity module. These results are encouraging for the treatment of ectatic corneas particularly below 400 μm. It is considered that the findings obtained from this study will guide future experimental and clinical studies.

Purpose: The purpose of this study was to report our first clinical experience using topical losartan for the treatment of severe corneal haze after epithelium-off corneal cross-linking (CXL)., Methods: A 20-year-old man presented with clinically significant corneal haze in the right eye 1 month following Ultraviolet-A/Riboflavin Epithelium-off Collagen CXL. Haze progressed to a deep stromal scar, and vision was 20/150 with no improvement on refraction, 60 days after CXL. After unsuccessful treatment with topical corticosteroids, the patient elected to start off-label treatment with topical losartan 0.8 mg/mL, administered 6 times per day., Results: After 3 months of initiating topical losartan, the right eye vision improved to preoperative vision of 20/40-1. Corneal haze was significantly reduced as observed on slitlamp examination and on Scheimpflug corneal tomography (Pentacam; OCULUS, Inc. Arlington, WA)., Conclusions: Topical losartan, a transforming growth factor-β inhibitor, is a potential treatment in clinically significant corneal haze following epithelium-off corneal CXL. This clinical experience highlights the potential efficacy of topical losartan as a novel therapeutic option in such cases, but further clinical studies are needed., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Bioluminescence resonance energy transfer photodynamic therapy, which uses light generated by bioluminescent proteins to activate photosensitizers and produce reactive oxygen species without the need for external irradiation, has shown promising results in cancer models. However, the characterization of delivery systems that can incorporate the components of this therapy for preferential delivery to the tumor remains necessary. In this work, we have characterized parvovirus B19-like particles (B19V-VLPs) as a platform for a photosensitizer and a bioluminescent protein. By chemical and biorthogonal conjugation, we conjugated rose Bengal photosensitizer and firefly luciferase to B19V-VLPs and a protein for added specificity. The results showed that B19V-VLPs can withstand decoration with all three components without affecting its structure or stability. The conjugated luciferase showed activity and was able to activate rose Bengal to produce singlet oxygen without the need for external light. The photodynamic reaction generated by the functionalized VLPs-B19 can decrease the viability of tumor cells in vitro and affect tumor growth and metastasis in the 4 T1 model. Treatment with functionalized VLPs-B19 also increased the percentage of CD4 and CD8 cell populations in the spleen and in inguinal lymph nodes compared to vehicle-treated mice. Our results support B19V-VLPs as a delivery platform for bioluminescent photodynamic therapy components to solid tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: To report two cases of persistent macular edema caused by the exudation of diabetic telangiectatic capillaries (TelCaps), which have been successfully treated with photodynamic therapy (PDT)., Methods: Review of data from two patients suffering from persistent macular edema caused by parafoveolar TelCaps. In both cases, conventional laser was impossible because TelCaps were to close from foveal center., Results: The use of focal PDT on perifoveolar TelCaps permitted to reduce persistent macular edema and to avoid inefficient intravitreal anti-vascular epithelial growth factor or steroid injections. In both cases, visual acuity was fully restored four to six months after PDT. Central macular thickness was also normalized in the first case and significantly reduced in the second case. In both cases, visual gain was sustained throughout the whole follow-up period (2 and 1 year, respectively)., Conclusion: Photodynamic therapy can be helpful to treat diabetic macular edema caused by TelCaps nonresponding to approved intravitreal therapy or for which conventional laser is contraindicated.

Purpose: To investigate predictors of recurrent exudation in choroidal neovascularization (CNV) of pachychoroid neovasculopathy after photodynamic therapy (PDT)., Methods: Consecutive, treatment-naïve, symptomatic patients with pachychoroid neovasculopathy with subfoveal retinal fluid treated with PDT and followed for 18 months were studied retrospectively. Choroidal neovascularization areas were calculated from optical coherence tomography angiography images obtained at various time points after the initial PDT., Results: In 52 eyes, the subfoveal retinal fluid resolved completely three months after PDT; in 23 (44%) eyes, exudation recurred during the 18-month follow-up period. In 29 eyes with no recurrence, the mean baseline square root of the CNV area of 1.91 mm (95% CI, 0.27) decreased significantly ( P = 0.006) to 1.47 mm (95% CI, 0.16) at three months after PDT and decreased further until 12 months after PDT (mean, 1.26 mm; 95% CI, P < 0.001) and was maintained thereafter. In 23 eyes with a recurrence, the square root of the CNV area enlarged significantly ( P = 0.028) from 1.43 mm (95% CI, 0.21) at examination three months before the recurrence to 1.73 mm (95% CI, 0.18) at recurrence., Conclusion: Choroidal neovascularization enlargement during the follow-up period after PDT for pachychoroid neovasculopathy may predict recurrence.

Recent research indicated that ulcers and peripheral vascular disease resulting from drug-resistant bacterial infections are the main causes of delayed healing in chronic diabetic wounds. 5-Aminolevulinic acid (ALA) is a second-generation endogenous photosensitizer. The therapeutic effect and mechanism of ALA-mediated photodynamic therapy (ALA-PDT) on methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds in diabetic rats were investigated in this study. The results revealed the promising antibacterial effects of ALA-PDT MRSA in vitro, with a minimum inhibitory concentration and minimum bactericidal concentration of 250 and 500 μM, respectively. ALA-PDT also changed the permeability and structural integrity of bacterial cell membranes by producing reactive oxygen species. Meanwhile, ALA-PDT accelerated wound healing in MRSA-infected diabetic rats, with 5 % ALA-PDT achieving complete sterilization in 14 days and wound closure in 21 days. Treatment with 5 % ALA-PDT additionally improved the histopathological appearance of skin tissue, as well as fibrosis, inflammatory cytokine release, and angiogenesis-related protein expression. These findings indicated that ALA-PDT significantly promoted the healing of MRSA-infected wounds in diabetic rats by eliminating bacteria, inhibiting inflammation, generating granulation tissues, promoting neovascularization, and restoring damaged nerves. In addition, the healing mechanism was related to the activation of inflammatory and angiogenesis pathways through the regulation of tumor necrosis factor-alpha and interleukin-6 expression and upregulation of CD206, CD31, and VEGF. These findings underscored the potential role of ALA-PDT in promoting the healing of chronic diabetic wounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To solve the problems existing in the clinical application of hypericin (Hyp) and tirapazamine (TPZ), a nano-drug delivery system with synergistic anti-tumor functions was constructed using mesoporous silica nanoparticles (MSN) and sodium alginate (SA). The system exhibited excellent stability, physiological compatibility and targeted drug release performance in tumor tissues. In the in vitro and in vivo experiments, Hyp released from MSN killed tumor cells through photodynamic therapy (PDT). The degree of hypoxia in the tumor tissue site was exacerbated, enabling TPZ to fully exert its anti-tumor activity. Our studies suggested that the synergistic effects between the components of the nano-drug delivery system significantly improve the anti-tumor properties of Hyp and TPZ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The urgent need for antimicrobial agents to combat infections caused by multidrug-resistant bacteria facilitates the exploration of alternative strategies such as photosensitizer (PS)-mediated photoinactivation. However, increasing studies have discovered uncorrelated bactericidal activities among PSs possessing similar photodynamic and pathogen-targeted properties. To optimize the photodynamic therapy (PDT) against infections, we investigated three type-I PSs of D-π-A AIEgens TI, TBI, and TTI. The capacities of reactive oxygen species (ROS) generation of TI, TBI, and TTI did not align with their bactericidal activities. Despite exhibiting the lowest photodynamic efficiency, TI exhibited the highest activities against methicillin-resistant Staphylococcus aureus (MRSA) by impairing the anti-oxidative responses of bacteria. By comparison, TTI, characterized by the strongest ROS production, inactivated intracellular MRSA by potentiating the inflammatory response of macrophages. Unlike TI and TTI, TBI, despite possessing moderate photodynamic activities and inducing ROS accumulation in both MRSA and macrophages, did not exhibit any antibacterial activity. Therefore, relying on the disturbed anti-oxidative metabolism of pathogens or potentiated host immune responses, transient ROS bursts can effectively control bacterial infections. Our study reevaluates the contribution of photodynamic activities of PSs to bacterial elimination and provides new insights into discovering novel antibacterial targets and agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Over the last decades, a variety of metal complexes have been developed as chemotherapeutic agents. Despite the promising therapeutic prospects, the vast majority of these compounds suffer from low solubility, poor pharmacological properties, and most importantly poor tumor accumulation. To circumvent these limitations, herein, the incorporation of cytotoxic Ir(III) complexes and a variety of photosensitizers into polymeric gemini nanoparticles that selectively accumulate in the tumorous tissue and could be activated by near-infrared (NIR) light to exert an anticancer effect is reported. Upon exposure to light, the photosensitizer is able to generate singlet oxygen, triggering the rapid dissociation of the nanostructure and the activation of the Ir prodrug, thereby initiating a cascade of mitochondrial targeting and damage that ultimately leads to cell apoptosis. While selectively accumulating into tumorous tissue, the nanoparticles achieve almost complete eradication of the cisplatin-resistant cervical carcinoma tumor in vivo upon exposure to NIR irradiation., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Antimicrobial photodynamic therapy (aPDT) has shown efficacy in inactivating different bacterial species by photosensitizer-induced free radical production. Despite aPDT is considered unable to cause resistant strains, enzymatic pathways for detoxification of reactive oxygen species and transmembrane photosensitizer efflux systems could cause resistance to aPDT. Resistance mechanisms can be evaluated by measurement of mRNA from by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Thus, the aim of this study was to access the mRNA level data obtained by RT-qPCR in bacterial cells submitted to photodynamic therapy. Studies performed on mRNA levels in bacteria after PDT were assessed on MEDLINE/Pubmed. The mRNA levels from genes related to various functions have been successfully evaluated in both Gram-positive and -negative bacteria after aPDT by RT-qPCR. Such an approach has improved the understanding of aPDT-induced effects, and reinforced the effectiveness of aPDT on bacteria, which can cause infections in different human tissues., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant lung tumors. The research on the mechanism of PDT mediated by hematoporphyrin derivatives (HPD) and its cytotoxic effects on lung cancer cells has primarily focused on lung adenocarcinoma cells. However, the impact of HPD-PDT on lung squamous cell carcinoma has not been thoroughly studied. This study aimed to investigate the effects of 630 nm laser on apoptosis, metastasis, invasion, and epithelial-mesenchymal transition (EMT) in human lung squamous cell carcinoma H520 cells mediated by HPD. H520 cells were divided into four groups: control group, photosensitizer group, irradiation group, and HPD-PDT group. Cell proliferation was assessed using CCK8 assay; cell apoptosis was detected by Hoechst 33258 staining and flow cytometry; cell migration and invasion abilities were evaluated using wound-healing and invasion assays; and protein and mRNA expressions were analyzed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) respectively. Results showed that HPD-PDT significantly inhibited cell proliferation, promoted apoptosis (P < 0.05), suppressed cell migration and invasion (P < 0.05), decreased Bcl-2 mRNA expression, and increased Bax and Caspase-9 mRNA expression(P < 0.05). Western blotting analysis indicated increased expression of Bax, Caspase-9, and E-cadherin, and decreased expression of Bcl-2, N-cadherin, and Vimentin (P < 0.05). In conclusion, 630 nm laser mediated by HPD promoted cell apoptosis via upregulation of Bax and caspase-9, and downregulation of Bcl-2, and inhibited cell migration and invasion by regulating EMT in H520 cells., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Esophageal cancer (EC) is a disease characterized by progressive malignant obstruction. Stent implantation restores lumen patency, but tumor progression is likely to cause re-occlusion shortly. An esophageal stent loaded with Ce6-SiO 2 @MnO 2 nanoparticles was designed, for which a dense δ-MnO 2 coating was synthesized using a novel one-step REDOX reaction. This stent reverses the hypoxic tumor microenvironment (TME) via explosive oxygen generation, thereby increasing the efficacy of photodynamic therapy (PDT). Furthermore, Mn 2+ reprograms the polarity of tumor associated macrophages (TAMs) in the immunosuppressed TME to effectively activate innate anti-tumor immunity in combination with PDT. Mn 2+ downregulates the high mobility group box 1 protein (HMGB1), upregulates the signal transducer and activator of transcription 1 (STAT1) mRNA, and ultimately expresses the tumor inhibition effect of TAMs. Additionally, Ce6-SiO 2 @MnO 2 effectively suppresses the apoptosis of TAMs to enhance their anti-tumor effect. The proposed strategy highlights the multifaceted role of Ce6-SiO 2 @MnO 2 in the treatment of advanced esophageal cancer.

The process of wound healing is a complex, multi-phase phenomenon crucial for optimal tissue regeneration. Traditional drug delivery systems often target specific phases of wound repair, neglecting the dynamic interplay among the stages. This limitation highlights the need for comprehensive delivery systems that cater to the holistic needs of wound healing, enhancing tissue regeneration efficiency. Herein, we explored the utility of platelet-derived extracellular vesicles (pEVs) as carriers for the phototherapeutic diferuloylmethane (DIF), resulting in a formulation termed DIF@pEVs, which is designed to sequentially address the distinct phases of wound healing. Initially, upon exposure to light, administered DIF@pEVs generate photodynamic therapy-derived reactive oxygen species during the early inflammatory phase. This generation of ROS aims to modulate the inflammatory response, induce the protective mechanisms of heat shock proteins, and kickstart the tissue regeneration process. Following this initial phase, the remaining DIF and pEVs persist in promoting tissue repair and regeneration. Ultimately, it reduces inflammation, speeds up the healing process, and promotes vascular and follicular formation in a model of burn wound skin damage, thereby supporting skin regeneration. The deployment of DIF@pEVs represents an advancement in regenerative medicine, providing a precise, versatile approach to fostering regeneration across a wide range of clinical scenarios.

Synergetic combination therapy is emerging as one of the most promising approaches for cancer treatment. Among the various therapeutic approaches, PDT has received particular attention due to its non-invasive nature. However, the therapeutic performance of PDT is severely affected by tumour hypoxia. Herein, we report a supramolecular strategy for the fabrication of a PDT-active 2D nanosheet loaded with a POD mimicking DNAzyme for the synergetic combination of PDT and CDT for targeted cancer therapy. Assembly of biotin-functionalized BODIPY (1) and cationic β-cyclodextrin (β-CD+) leads to the formation of a 1/β-CD+ nanosheet with positively charged β-CD+ on the surface of the sheet. The cationic face of the 1/β-CD+ sheet was then loaded with a POD-mimicking Hem-loaded G-quadruplex aptamer (Hem/DNA1) via electrostatic interactions (1/β-CD+/Hem/DNA1). Cellular internalization of the 1/β-CD+/Hem/DNA1 nanosheet occurs via a receptor-mediated endocytic pathway, which then undergoes lysosomal escape. Subsequently, Hem/DNA1 on the surface of 1/β-CD+/Hem/DNA1 reacts with endogenous H 2 O 2 via the Fenton pathway to produce ˙OH and O 2 . Moreover, under cellular conditions, Hem inside the 1/β-CD+/Hem/DNA1 nanosheet produces Fe 2+ , which then undergoes another Fenton reaction to produce ˙OH and O 2 . The Fe 3+ generated after the Fenton reaction is then reduced in situ to Fe 2+ by glutathione for the next Fenton cycle. At the same time, photoirradiation of the 1/β-CD+ nanosheet using a 635 nm laser produces 1 O 2 via the PDT pathway by using endogenous O 2 . The most remarkable feature of the present nanoformulation is the cooperativity in its therapeutic action, wherein O 2 produced during the CDT pathway was used by the 1/β-CD+ sheet for improving its PDT efficacy in the hypoxic tumor microenvironment. This work represents a unique combination of CDT and PDT for targeted cancer therapy, wherein the CDT action of the nanoagent enhances the PDT efficacy and we strongly believe that this approach would encourage researchers to design similar combination therapy for advancements in the treatment of cancer.

Background: Infectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro rose bengal photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates (Atalay HT et al., Curr Eye Res 43:1322-5, 2018, Arboleda A et al. Am J Ophthalmol 158:64-70, 2014). In one published series, RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthamoeba keratitis not responsive to medical therapy., Methods: This international, randomized, sham and placebo controlled 2-arm clinical trial randomizes patients with smear positive fungal and acanthamoeba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) topical antimicrobial plus sham RB-PDT or 2) topical antimicrobial plus RB-PDT., Discussion: We anticipate that RB-PDT will improve best spectacle-corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via ClinicalTrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request., Trial Registration: NCT, NCT05110001 , Registered on November 5, 2021., (© 2024. The Author(s).)

As a novel therapeutic approach, photothermal therapy (PTT) combined with chemotherapy can synergistically produce antitumor effects. Herein, dithiodipropionic acid (DTDP) was used as a donor of disulfide bonds sensitive to the tumor microenvironment for establishing chemical bonding between the photosensitizer indocyanine green amino (ICG-NH 2 ) and acidified single-walled carbon nanotubes (CNTs). The CNT surface was then coated with conjugates (HD) formed by the targeted modifier hyaluronic acid (HA) and 1,2-tetragacylphosphatidyl ethanolamine (DMPE). After doxorubicin hydrochloride (DOX), used as the model drug, was loaded by CNT carriers, functional nano-delivery systems (HD/CNTs-SS-ICG@DOX) were developed. Nanosystems can effectively induce tumor cell (MCF-7) death in vitro by accelerating cell apoptosis, affecting cell cycle distribution and reactive oxygen species (ROS) production. The in vivo antitumor activity results in tumor-bearing model mice, further verifying that HD/CNTs-SS-ICG@DOX inhibited tumor growth most significantly by mediating a synergistic effect between chemotherapy and PTT, while various functional nanosystems have shown good biological tissue safety. In conclusion, the composite CNT delivery systems developed in this study possess the features of high biocompatibility, targeted delivery, and responsive drug release, and can achieve the efficient coordination of chemotherapy and PTT, with broad application prospects in cancer treatment.

The penetration ability of visible light (<2 mm) and near-infrared (NIR) light (∼1 cm) remarkably impairs the therapeutic efficacy and clinical applications of photodynamic therapy (PDT). To address the limitation of light penetration depth, a novel self-luminescent bacterium, teLuc.FP-EcN, has been engineered through transfection of a fusion expression plasmid containing the luciferase gene teLuc and bright red fluorescent protein mScarlet-I into Escherichia coli Nissle 1917 ( EcN ). The engineered teLuc.FP-EcN can specifically target and colonize tumors without significant toxicity to the host. Acting as a continuous internal light source, teLuc.FP-EcN can activate the photosensitizer chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and then effectively destroy tumor tissue from the inside. As a result, a significant reduction in tumor proliferation and extension of the overall survival in mouse tumor models has been observed. Furthermore, teLuc.FP-EcN-boosted PDT amplified its therapeutic effect by activating antitumor immune response, including the conversion of M2 macrophages into pro-inflammatory M1 macrophages, as well as an increase in the proportion of CD3 + T cells and a decrease in T-cell exhaustion. In conclusion, teLuc.FP-EcN can be used as an implantable light source for tumor phototherapy, which simultaneously possesses ROS generation and immune regulation.

Photothermal therapy (PTT) is a method for eradicating tumor tissues through the use of photothermal materials and photosensitizing agents that absorb light energy from laser sources and convert it into heat, which selectively targets and destroys cancer cells while sparing healthy tissue. MXenes have been intensively investigated as photosensitizing agents for PTT. However, achieving the selectivity of MXenes to the tumor cells remains a challenge. Specific antibodies (Ab) against tumor antigens can achieve homing of the photosensitizing agents toward tumor cells, but their immobilization on MXene received little attention. Here, we offer a strategy for the selective ablation of melanoma cells using MXene-polydopamine-antiCEACAM1 Ab complexes. We coated Ti 3 C 2 T x MXene with polydopamine (PDA), a natural compound that attaches Ab to the MXene surface, followed by conjugation with an anti-CEACAM1 Ab. Our experiments confirm the biocompatibility of the Ti 3 C 2 T x -PDA and Ti 3 C 2 T x -PDA-antiCEACAM1 Ab complexes across various cell types. We also established a protocol for the selective ablation of CEACAM1-positive melanoma cells using near-infrared irradiation. The obtained complexes exhibit high selectivity and efficiency in targeting and eliminating CEACAM1-positive melanoma cells while sparing CEACAM1-negative cells. These results demonstrate the potential of MXene-PDA-Ab complexes for cancer therapy. They underline the critical role of targeted therapies in oncology, offering a promising avenue for the precise and safe treatment of melanoma and possibly other cancers characterized by specific biomarkers. Future research will aim to refine these complexes for clinical use, paving the way for new strategies for cancer treatment.

A wide variety of methods are being developed to ultimately defeat cancer; while some of these strategies have shown highly positive results, there are serious obstacles to overcome to completely eradicate this disease. So, it is crucial to construct multifunctional nanostructures possessing intelligent capabilities that can be utilized to treat cancer. A possible strategy for producing these multifunctional nanostructures is to combine various cancer treatment techniques. Based on this point of view, we successfully synthesized multifunctional HCuS@Cu 2 S@Au-P(NIPAM- co -AAm)-PpIX nanohybrids. The peculiarities of these thermosensitive polymer-modified and protoporphyrin IX (PpIX)-loaded hollow nanohybrids are that they combine photodynamic therapy (PDT), sonodynamic therapy (SDT), and photothermal therapy (PTT) with an intelligent design. As an all-in-one nanohybrids, HCuS@Cu 2 S@Au-P(NIPAM- co -AAm)-PpIX nanohybrids were employed in the SDT-PDT-PTT combination therapy, which proved to have a synergistic therapeutic effect for in vitro tumor treatments against breast tumors.

Prostate cancer presents as a challenging disease, as it is often characterized as an immunologically "cold" tumor, leading to suboptimal outcomes with current immunotherapeutic approaches in clinical settings. Photodynamic therapy (PDT) harnesses reactive oxygen species generated by photosensitizers (PSs) to disrupt the intracellular redox equilibrium. This process induces DNA damage in both the mitochondria and nucleus, activating the process of immunogenic cell death (ICD) and the cGAS-STING pathway. Ultimately, this cascade of events leads to the initiation of antitumor immune responses. Nevertheless, existing PSs face challenges, including suboptimal tumor targeting, aggregation-induced quenching, and insufficient oxygen levels in the tumor regions. To this end, a versatile bionic nanoplatform has been designed for the simultaneous delivery of the aggregation-induced emission PS TPAQ-Py-PF 6 and paclitaxel (PTX). The cell membrane camouflage of the nanoplatform leads to its remarkable abilities in tumor targeting and cellular internalization. Upon laser irradiation, the utilization of TPAQ-Py-PF 6 in conjunction with PTX showcases a notable and enhanced synergistic antitumor impact. Additionally, the nanoplatform has the capability of initiating the cGAS-STING pathway, leading to the generation of cytokines. The presence of damage-associated molecular patterns induced by ICD collaborates with these aforementioned cytokines lead to the recruitment and facilitation of dendritic cell maturation. Consequently, this elicits a systemic immune response against tumors. In summary, this promising strategy highlights the use of a multifunctional biomimetic nanoplatform, combining chemotherapy, PDT, and immunotherapy to enhance the effectiveness of antitumor treatment.

Background: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution., Methods: We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks., Results: The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway., Conclusions: Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy., Competing Interests: None.

As a precursor of protoporphyrin IX (PpIX), an endogenous pro-apoptotic and fluorescent molecule, 5-Aminolevulinic acid (5-ALA) has gained substantial attention for its potential in fluorescence-guided surgery as well as photodynamic therapy (PDT). Moreover, 5-ALA-PDT has been suggested as a promising chemo-radio sensitization therapy for various cancers. However, insufficient 5-ALA-induced PpIX fluorescence and the induction of multiple resistance mechanisms may hinder the 5-ALA-PDT clinical outcome. Reduced efficacy and resistance to 5-ALA-PDT can result from genomic alterations, tumor heterogeneity, hypoxia, activation of pathways related to cell surveillance, production of nitric oxide, and most importantly, deregulated 5-ALA transporter proteins and heme biosynthesis enzymes. Understanding the resistance regulatory mechanisms of 5-ALA-PDT may allow the development of effective personalized cancer therapy. Here, we described the mechanisms underlying resistance to 5-ALA-PTD across various tumor types and explored potential strategies to overcome this resistance. Furthermore, we discussed future approaches that may enhance the efficacy of treatments using 5-ALA-PDT., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. All authors have been participated in the preparation of the manuscript, and have given their agreement to submit this manuscript in the present format., (Copyright © 2024. Published by Elsevier Inc.)

Nanobodies (Nbs), the smallest antigen-binding fragments with high stability and affinity derived from the variable domain of naturally occurring heavy-chain-only antibodies in camelids, have been shown as an efficient way to improve the specificity to tumors for photodynamic therapy (PDT). Nonetheless, the rapid clearance of Nbs in vivo restricts the accumulation and retention of the photosensitizer at the tumor site causing insufficient therapeutic outcome, especially in large-volume tumors. Herein, we develop photodynamic conjugates, MNB-Pyra Nbs, through site-specific conjugation between 7D12 Nbs and type I photosensitizer MNB-Pyra (morpholine-modified nile blue structure connected to pyrazolinone) in a 1:2 ratio. The photosensitizers with long-term retention can be released at the tumor site by reactive oxygen species cleavage after illumination, accompanied with fluorescence recovery for self-reporting the occurrence of PDT. Ultimately, a single dose of MNB-Pyra Nbs demonstrate highly effective tumor suppression with high biosafety in the large-volume tumor models after three rounds of PDT. This nanobody conjugate provides a paradigm for the design of precise long-time retention photosensitizers and is expected to promote the development of PDT., (© 2024. The Author(s).)

Conventional nanomedicines typically employ a significant amount of excipients as carriers for therapeutic delivery, resulting in generally low drug-loading and compromised anti-cancer efficacy. Here, we propose a small-molecule nanomedicine (CMC NP) directly assembled using a chemotherapeutic drug (chlorambucil, CBL) and a phototherapeutic agent (chlorin e6, Ce6), and stabilized by metal coordination. The CMC NP exhibits exceptionally high drug loading (89.21%), robust stability, and smart disassembly in response to glutathione (GSH). Such a straightforward yet multifunctional delivery strategy could be a better alternative to overcome the above shortcomings of conventional nanomedicines while achieving enhanced efficacy. The CMC NP not only directly induces CBL-induced chemotherapy but also elicits synergistic antitumor responses through Ce6-mediated photodynamic and photothermal therapies. Owing to the multifaceted efforts from photodynamic, photothermal and chemo-therapies, the CMC NP exhibits excellent antitumor efficacy with negligible systemic toxicity which is untenable in traditional CBL-induced chemotherapy. Therefore, this study provides a feasible strategy for overcoming existing challenges and presents a potential opportunity to augment the clinical therapeutic effectiveness associated with conventional nanomedicine.

Endometrial cancer is the most common malignant tumor of the female reproductive system. It develops in the mucous membrane lining the inside of the uterine body-the endometrium, through the abnormal and continuous growth of cancer cells originating from the uterine mucosa. In recent years, there has been a significant increase in the number of cases in European countries. Photodynamic therapy (PDT) is an innovative and dynamically developing medical procedure, useful in the treatment of cancer and non-cancer tissue conditions. The PDT reaction involves the activation of a photosensitizing substance with visible light, which in turn leads to the formation of free oxygen radicals, which contribute to the destruction of the cell. PDT is minimally invasive, has few side effects, and preserves organ anatomy and function. Both diagnostics and photodynamic therapy as modern methods of treatment are becoming more and more popular in many research units around the world. They are most often practiced and tested in in vitro experimental conditions. In clinical practice, the use of PDT is rare. Comprehensive cooperation between scientists contributes to taking steps towards obtaining new, synthetic photosensitizers, directing their physicochemical properties, and showing the impact on a given organism. This review examines the evidence for the potential and usefulness of PDT in the treatment of endometrial cancer. This review highlights that PDT is gaining popularity and is becoming a promising field of medical research.

Gliomas account for 24% of all the primary brain and Central Nervous System (CNS) tumors. These tumors are diverse in cellular origin, genetic profile, and morphology but collectively have one of the most dismal prognoses of all cancers. Work is constantly underway to discover a new effective form of glioma therapy. Photodynamic therapy (PDT) may be one of them. It involves the local or systemic application of a photosensitive compound-a photosensitizer (PS)-which accumulates in the affected tissues. Photosensitizer molecules absorb light of the appropriate wavelength, initiating the activation processes leading to the formation of reactive oxygen species and the selective destruction of inappropriate cells. Research focusing on the effective use of PDT in glioma therapy is already underway with promising results. In our work, we provide detailed insights into the molecular changes in glioma after photodynamic therapy. We describe a number of molecules that may contribute to the resistance of glioma cells to PDT, such as the adenosine triphosphate (ATP)-binding cassette efflux transporter G2, glutathione, ferrochelatase, heme oxygenase, and hypoxia-inducible factor 1. We identify molecular targets that can be used to improve the photosensitizer delivery to glioma cells, such as the epithelial growth factor receptor, neuropilin-1, low-density lipoprotein receptor, and neuropeptide Y receptors. We note that PDT can increase the expression of some molecules that reduce the effectiveness of therapy, such as Vascular endothelial growth factor (VEGF), glutamate, and nitric oxide. However, the scientific literature lacks clear data on the effects of PDT on many of the molecules described, and the available reports are often contradictory. In our work, we highlight the gaps in this knowledge and point to directions for further research that may enhance the efficacy of PDT in the treatment of glioma.

Background: Glutathione (GSH), a highly abundant thiol compound within cells, plays a critical role in physiological processes and exhibits close correlation with cancer. Among molecular imaging technologies, most probes have relatively short emission wavelengths and lack photoacoustic imaging (PA) capability, resulting in the inability to obtain tissue images with high penetration depth. The presence of GSH in the tumor microenvironment neutralizes ROS, diminishing the therapeutic effect of PDT, thus resulting in often unsatisfactory therapeutic efficacy. Therefore, it is imperative to develop a dual-modal probe for the detection of GSH and the diagnosis and treatment of cancer., Results: In this study, we synthesized a novel dual-modal probe, Cy-Bio-GSH, utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging techniques for GSH detection. The probe integrates cyanine dye as the fluorophore, nitroazobenzene as the recognition moiety, and biotin as the tumor-targeting moiety. Upon reacting with GSH, the probe emits NIR fluorescence at 820 nm and generates a PA signal. Significantly, this reaction activates the photodynamic and photothermal properties of the probe. By depleting GSH and employing a synergistic photothermal therapy (PTT) treatment, the therapeutic efficacy of photodynamic therapy (PDT) is remarkably enhanced. In-vivo experiments confirm the capability of the probe to detect GSH via NIRF and PA imaging. Notably, the combined tumor-targeting ability and PDT/PTT synergistic therapy enhance therapeutic outcomes for tumors and facilitate their ablation., Significance: A novel tumor-targeting and dual-modal imaging probe (Cy-Bio-GSH) is synthesized, exhibiting remarkable sensitivity and selectivity to GSH, enabling the visualization of GSH in cells and the differentiation between normal and cancer cells. Cy-Bio-GSH enhances PDT/PTT with effective killing of cancer cells and makes the ablation of tumors in mice. This work represents the first tumor-targeting probe for GSH detection, and provides crucial tool for cancer diagnosis and treatment by dual-modal imaging with improved PDT/PTT synergistic therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is a promising anticancer method due to its noninvasive features, high efficiency, and superior accuracy. The activated near-infrared upconversion photosensitizer has a high tissue penetration depth and could be explicitly released with minimal side effects. Therefore, we designed and synthesized a series of Br-substituted compounds (NFh-Br) based on the near-infrared upconversion hemicyanine dye. The heavy atomic effect improves the generation of 1 O 2 and upconversion luminous efficiency. Especially, NFh-Br 11 exhibited an excellent 1 O 2 generation rate under 808 nm excitation and effectively killed tumor cells in vitro, and the alkaline phosphatase (ALP)-activatable photosensitizer (NFh-ALP) was obtained by modifying the NFh-Br 11 . NFh-ALP could be activated by ALP and release NFh-Br 11 , which induces apoptosis of tumor cells and has outstanding anticancer effects in vitro and in vivo. This work could provide a strategy for designing activatable upconversion photosensitizers.

The perfect integration of microbubbles for efficient ultrasound imaging and nanocarriers for intelligent tumor-targeting delivery remains a challenge in precise tumor theranostics. Herein, we exquisitely fabricated laser-activated and targeted polymersomes (abbreviated as FIP-NPs) for simultaneously encapsulating the photosensitizer indocyanine green (ICG) and the phase change agent perfluorohexane (PFH). The formulated FIP-NPs were nanosize and effectively accumulated into tumors as observed by ICG fluorescence imaging. When the temperature rose above 56 °C, the encapsulated PFH transformed from liquid to gas and the FIP-NPs underwent balloon-like enlargement without structure destruction. Impressively, the enlarged FIP-NPs fused with adjacent polymersomes to form even larger microparticles. This temperature-responsive "nano-to-micro" transformation and fusion process was clearly demonstrated, and FIP-NPs showed greatly improved ultrasound signals. More importantly, FIP-NPs achieved dramatic antitumor efficacy through ICG-mediated phototherapy. Taken together, the novel polymersomes achieved excellent ultrasound/fluorescence dual imaging-guided tumor phototherapy, providing an optimistic candidate for the application of tumor theranostics.