As society evolves, individuals increasingly prioritize their health, leading to heightened demands for disease diagnosis and treatment. The pursuit of high-quality and efficient treatment is essential for achieving this goal. As an emerging treatment strategy, photodynamic therapy (PDT) has been proven to be a minimally invasive therapy with strong controllability and spatiotemporal resolution, demonstrating notable clinical potential in anti-cancer and anti-infection treatment.

The therapeutic agent in PDT, known as a photosensitizer (PS), operates through a mechanism illustrated through the Jablonski energy level diagram (Fig. 1). Under appropriate wavelength light irradiation, PSs become excited from the ground state (S₀) to the singlet excited state. Among these excited states, the lowest singlet state (S₁) plays a crucial role in subsequent photophysical processes, following Kasha’s rule. When excitons return to their ground state through radiative transitions, they release fluorescence, which enables PS localization and provides guidance for subsequent PDT. Excitons can also transition from S₁ to the lowest triplet state (T₁) through an intersystem crossing (ISC) process, subsequently generating reactive oxygen species (ROS). These reactive oxygen species oxidize surrounding biomolecules and produce cytotoxicity in target cells or bacteria. In addition, PSs in the excited state can return to S₀ through non-radiative decay, generating heat and achieving a combination of photothermal therapy (PTT) and PDT in some special cases.

Despite significant advancements in PDT during recent years, PSs still commonly feature planar conjugated structures, resulting in high hydrophobicity. This characteristic means that PS degradation or elimination often requires extended periods after PDT. During this period, residual PSs may continue generating reactive oxygen species upon natural light exposure, potentially damaging normal cells and tissues, and eliciting acute inflammatory responses and side effects, thereby limiting their clinical utilization. This review focuses on the safety aspects of PSs in phototherapy, using representative cases to analyze general strategies for enhancing their metabolism and degradability via rational molecular design.

Enhancing the metabolic potential of PSs can effectively mitigate postoperative adverse effects. The kidney, a crucial organ in human physiology, serves as a primary filter for metabolic waste and reabsorption of essential substances, thereby preserving internal homeostasis. PSs designed for renal clearance must address postoperative excretion requirements, with their size remaining below the renal filtration threshold of approximately 6 nm for effective renal metabolism. A prevalent approach to enhancing renal clearance (RCE) of PSs involves incorporating one or more hydrophilic moieties, including polyethylene glycol (PEG) chains (Fig. 2), charges (Fig. 3), and morpholine group (Fig. 4), to control the morphologies and sizes in physiological environments to satisfy the requirements of renal metabolism. A recent alternative approach involves constructing PSs using readily oxidizable groups, which upon oxidation form polar bonds, thereby enhancing the hydrophilicity of the product and subsequently accelerating the metabolic rate of the PSs (Fig. 5).

In recent years, degradable PSs have been proposed that can undergo degradation via ROS oxidation following diagnosis or treatment, thereby mitigating potential side effects. Furthermore, the degradation products exhibit smaller sizes than their precursors, facilitating expedited elimination from the body. A common strategy for designing such degradable PSs, apart from employing supramolecular approaches (Fig. 6), involves introducing π-conjugated bridges susceptible to oxidation and rupture into PSs, exemplified by methyl imidazole (Fig. 7), anthracene bridges (Fig. 8), conjugated double bonds (Fig. 9), and diketopyrrole (Figs. 10 and 11). Generally, the degradation process encompasses self-degradation and biodegradation. In the self-degradation process, PSs degrade through self-generated ROS upon excitation, while biodegradable PSs undergo degradation by endogenous ROS, leading to different application scopes: self-degradable PSs are suitable for intratumoral administration, while biodegradable PSs are suitable for systemic administration. Recent development of PSs with both degradation modes (Fig. 12) ensures complete degradation, further enhancing postoperative safety. Besides above examples, researchers report the use of unstable non-conjugated linkers to construct degradable pseudo-conjugated polymers (Fig. 13). For this type of PSs, degradation is unlikely to destroy the conjugated structure, thereby accelerating metabolism without function loss, which is an effective strategy to improve PDT safety.

In this study, the latest advances in improving the metabolism or degradability of PSs to enhance PDT safety are reviewed. Generally, introducing highly hydrophilic groups onto PSs to control their morphologies and sizes in physiological environments is the most commonly used method to improve their renal clearance rate, while using easily oxidizable conjugated units (such as methyl imidazole and anthracene ring) as conjugated bridges to construct PSs is key to endowing them with degradability. In theory, the approach of “degradation first, followed by metabolism” appears advantageous over metabolism alone, because PSs quickly lose their photosensitization during degradation, resulting in reduced impact on the human body post-PDT. In addition, organisms eliminate the degradation products more easily. However, it is important to note that the metabolizable or biodegradable PSs remain in the laboratory study phase. Before clinical promotion, their detailed biocompatibility, pharmacokinetics, detailed metabolic pathways, long-term side effects, etc. require strict evaluation, which is a time-consuming and expensive task. As concluding remarks, we expect that this review will inspire the development of PSs with heightened biosafety profiles.