Small molecule photosensitizers: Paving the way for improved photodynamic therapy in dermatology

The skin, the largest and most exposed organ, plays a vital role in protecting internal organs and regulating metabolic processes. Dermatological diseases such as psoriasis, acne, and skin cancer significantly affect patients' quality of life and present considerable therapeutic challenges. Conventional treatments often suffer from limitations, including side effects, low efficacy, invasiveness, and high costs, underscoring the need for alternative, non-invasive therapies. Photodynamic therapy (PDT) has emerged as a promising, selective, and minimally damaging approach for treating skin diseases. PDT relies on photosensitizers that, upon light activation, generate reactive oxygen species (ROS) to selectively damage affected cells. However, PDT is constrained by issues such as poor solubility, low photostability, and inadequate tissue targeting. Recent advances in small molecule photosensitizers, including FDA-approved agents and those in clinical trials, have addressed these limitations by enhancing solubility, stability, and targeting capabilities. The integration of nanotechnology, particularly nanocarriers, further improves PDT efficacy by enhancing delivery and enabling deeper penetration of photosensitizers. This review examines recent developments in small molecule-based PDT, with a focus on photosensitizer modifications, their photophysical properties, and strategies to optimize solubility, stability, and targeting. The role of nanocarriers in enhancing delivery and the challenges in clinical application of PDT are also discussed.