Photodynamic inactivation and photodynamic therapy for viral pathogens: a systematic review of antiviral efficacy, mechanisms, and translational boundaries

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BACKGROUND AND AIM: Viral infections pose a persistent global threat, driven by emerging pathogens and rising antiviral resistance. Photodynamic inactivation (PDI) and photodynamic therapy (PDT) generate reactive oxygen species via a photosensitizer (PS) and light, offering broad-spectrum antiviral potential. However, evidence on efficacy remains fragmented and spans mechanistically distinct applications ranging from ex vivo pathogen reduction to localized clinical treatment. This systematic review synthesizes available data on photosensitizer-mediated antiviral effects, therapeutic applications, and limitations, explicitly distinguishing PDI (ex vivo/environmental inactivation) from PDT (in vivo treatment). METHODS: This systematic review was conducted in accordance with PRISMA 2020 guidelines. A comprehensive literature search was performed in PubMed, Scopus, Web of Science, and Embase for studies published between January 1990 and April 2026. Peer-reviewed original articles evaluating the antiviral effects of photosensitizer-mediated PDI or PDT in vitro, in vivo, or in clinical settings were included. Studies employing direct UV irradiation without a photosensitizer or light-independent antiviral mechanisms were excluded from the primary evidence synthesis. Two reviewers independently screened studies, assessed eligibility, and extracted data. Due to substantial heterogeneity in viral targets, photosensitizers (PSs), light parameters, and outcome measures, findings were synthesized narratively. Risk of bias was assessed using design-appropriate tools. RESULTS: Of 242 records, 30 studies (22 in vitro/ex vivo, 4 animal, and 4 clinical) were included. PDI achieved multi-log reductions against enveloped viruses, while non-enveloped viruses required higher PS concentrations and light doses. Common PSs included methylene blue, porphyrins, phthalocyanines, and Rose Bengal, riboflavin, and ruthenium complexes. Based on the limited and heterogeneous clinical data available, the safety profile of PDI in transfusion-related applications and PDT in mucocutaneous applications appears promising but remains to be conclusively established. CONCLUSION: Photosensitizer-mediated PDI exhibits potent in vitro antiviral activity, particularly against enveloped viruses, through oxidative damage to viral components. However, the evidence is almost entirely preclinical, and current evidence does not support conventional PDT as a clinically feasible treatment for systemic viremia; its most realistic antiviral applications remain localized accessible infections and ex vivo pathogen reduction. Future extracorporeal or targeted light-delivery strategies may eventually expand these boundaries, but no such approach has yet been clinically validated. Further clinical studies are warranted for specific indications, particularly ex vivo blood product decontamination and localized mucocutaneous infections.