Adjunctive Strategies to Enhance Antimicrobial Photodynamic Therapy in Oral Infections: A Systematic Review of Randomized Controlled Trials

Background/Objectives: Antimicrobial photodynamic therapy (aPDT) is a widely investigated adjunct for managing oral biofilm-associated bacterial and fungal infections, but poor photosensitizer penetration, aggregation, biofilm hypoxia, and protocol variability limit its clinical efficacy. Methods: This review was registered with PROSPERO (CRD420251207522) and conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library were searched for English-language RCTs. Eligible studies evaluated aPDT combined with physicochemical, delivery-based, light-based, biological, or host-modulating adjuncts in patients with oral biofilm-related bacterial or fungal disease, using an appropriate comparator. Data were synthesized narratively due to substantial clinical and methodological heterogeneity, and risk of bias was assessed using RoB 2. Results: Fourteen RCTs were included, predominantly addressing periodontal and peri-implant conditions, with additional studies involving orthodontic biofilms; no eligible RCT evaluated a fungal oral infection. Surfactant-based enhancement (e.g., sodium dodecyl sulfate) produced formulation- and protocol-dependent effects, with benefits reported for methylene blue and curcumin but not riboflavin. Nanocarrier-based photosensitizer delivery, evaluated in combination with Aloe vera vehicles, improved selected clinical outcomes without consistently superior microbiological effects; however, the independent contribution of the nanocarrier could not be isolated from the potential bioactive effects of the vehicle. An oxygen-releasing adjunct showed no significant between-group clinical benefit. Repeated dual-light irradiation improved bleeding on probing and pocket-related outcomes in some but not all trials. Probiotics, vitamin D, and low-level laser therapy showed inconsistent or preliminary benefits, each supported by limited trial numbers. Risk-of-bias assessments predominantly indicated low risk or some concerns, with one study judged at high overall risk. Conclusions: Enhancement of aPDT should not be regarded as a single therapeutic concept; its clinical benefit is strategy-, formulation-, and context-dependent. Current randomized evidence does not support a universally superior adjunct, highlighting the need for standardized, adequately powered trials with mechanism-oriented comparator designs.