Photodynamic therapy (PDT) is an effective treatment modality for different types of cancer, vascular-related diseases, and microbiological infections. PDT uses photosensitizer (PS), the light of a specific wavelength, and molecular oxygen to produce highly toxic reactive oxygen species (ROS), which causes cell death via different mechanisms such as vessel constriction, immunological response, and cell damage by apoptosis, autophagy, and necrosis pathways. Fundamental studies of PDT suggest that ROS yield can be affected by various factors such as transportation efficiency and tumor-targeting ability of PSs, illumination strategy of excitation sources, oxygen supply or dependence of the ROS-generation process, and combination with other therapeutic methods, hence directly determining the therapeutic efficacy. Additionally, the relationship between treatment dose and PDT efficacy is still under investigation. The evaluation for PDT indirectly but considerably affects the PDT efficacy by accurately monitoring dosimetric parameters of PDT, which is followed by efficiently regulating and upgrading the therapeutic scheme. In this study, the recent advances in PSs, light sources, tissue oxygenation, synergistic treatment, and dosimetry for improving the clinical PDT efficacy are summarized.

Several novel PSs such as C₆₀, black phosphorus, graphene quantum dots, and PSs with aggregation-induced emission, have been developed to improve the quantum yield of ¹O₂. The delivery efficiency of PSs has been improved by different PS delivery strategies and the tumor-microenvironment-responsive release scheme. PS absorption has been enhanced by organelle targeting and photochemical internalization, and PS hypoxia resistance has been resolved through loading with oxygen carriers or oxygen-generating reactants. Further, PS development with the synergistic therapeutic function will be used to enhance PDT efficacy.

As for PDT excitation sources, solar light, broad-spectrum lamps, lasers, light-emitting diodes (LEDs), X-ray sources, ultrasonic sources, and in vivo self-excited light sources capable of bioluminescence, chemiluminescence and Cherenkov light, have been widely studied. LEDs and lasers are the most popular light sources in clinical practice. Particularly, wearable, implantable, and disposable PDT light sources have progressed significantly because of the development of inorganic LED arrays, flexible LEDs, and wireless-driven LEDs. Further, in vivo self-excited light source has been studied to eliminate the absorption and scattering of light by biological tissues. Additionally, new illumination schemes of light fractionation and metronomic PDTs have been proposed to ensure oxygen supply during PDT treatment.

Oxygen carriers with high oxygen storage capacity or the chemical reaction substance can be delivered to the target lesion for in situ oxygen generation, which is the most popular method of enhancing oxygen supply for PDT. Additionally, hypoxia-activated linkers or prodrugs have been used to compensate for the low efficacy caused by hypoxia. However, reducing oxygen consumption during PDT can be achieved by limiting certain oxygen-consuming intracellular chemical reactions or reducing oxygen dependence using types Ⅰ or Ⅲ PDT.

To improve the therapeutic efficacy, PDT has been combined with clinical surgery, radiotherapy, chemotherapy, photothermal therapy, sonodynamic therapy, magnetic hyperthermia, and immunotherapy. Three or more modes for synergistic treatment with PDT have been presented. Further, simultaneously employing two PSs targeting different subcellular organelle is also employed to improve PDT efficacy.

Advanced optical imaging techniques such as hyperspectral imaging, Doppler optical coherence tomography, photoacoustic imaging measurement, and ¹O₂ luminescence imaging have been used successfully to monitor the dosimetric parameters from the original single-point/point-by-point signal acquisition to 2D imaging. The development of the detector has significantly improved the sensitivity, resolution, field of view, and speed of the optical imaging system. For example, the spatiotemporal detection of ¹O₂ luminescence can be accomplished by combining time-resolved scanning imaging and steady-state wide-field imaging.

Clinical applications of PDT are primarily used for tumor-, vascular-, and microbial-targeting treatments. Vascular-targeting PDT has been successfully demonstrated for treating vascular-related diseases such as age-related macular degeneration and port-wine stain. Additionally, PDT is effective against bacteria, viruses, and fungi in clinical applications.

Despite its clinical effectiveness, PDT is currently underutilized because of the non-fully satisfied and expensive PS, unclear dose-efficiency relationship, and difficulties in translating proof-of-principle research. To further improve PDT efficacy, ongoing research is being pursued to develop the multifunctional nano-PS, wearable LED and self-excited light sources, and the spatiotemporal multimodal optical imaging platform for monitoring and optimizing dosimetric parameters for pre-, during-, and post-PDT.