Natural photosensitizers (PS) are compounds derived from nature, with photodynamic properties. Natural PSs have a similar action to that of commercial PSs, where cancer cell death occurs by necrosis, apoptosis, and autophagy through ROS generation. Natural PSs have garnered great interest over the last few decades because of their high biocompatibility and good photoactivity. Specific wavelengths could cause phytochemicals to produce harmful ROS for photodynamic therapy (PDT). However, natural PSs have some shortcomings, such as reduced solubility and lower uptake, making them less appropriate for PDT. Nanotechnology offers an opportunity to develop suitable carriers for various natural PSs for PDT applications. Various nanoparticles have been developed to improve the outcome with enhanced solubility, optical adsorption, and tumor targeting. Multidrug resistance (MDR) is a phenomenon in which tumor cells develop resistance to a wide range of structurally and functionally unrelated drugs. Over the last decade, several researchers have extensively studied the effect of natural PS-based photodynamic treatment (PDT) on MDR cells. Though the outcomes of clinical trials for natural PSs were inconclusive, significant advancement is still required before PSs can be used as a PDT agent for treating MDR tumors. This review addresses the increasing literature on MDR tumor progression and the efficacy of PDT, emphasizing the importance of developing new nano-based natural PSs in the fight against MDR that have the required features for an MDR tumor photosensitizing regimen.

Background: The significant expansion of nanobiotechnology and nanomedicine has led to the development of innovative and effective techniques to combat various pathogens, demonstrating promising results with fewer adverse effects. Metal peroxide nanoparticles stand out among the crucial yet often overlooked types of nanomaterials, including metals. These nanoparticles are key in producing oxygen (O₂) and hydrogen peroxide (H₂O₂) through simple chemical reactions, which are vital in treating various diseases. These compounds play a crucial role in boosting the effectiveness of different treatment methods and also possess unique properties due to the addition of metal ions. Methods: This review discusses and analyzes some of the most common metal peroxide nanoparticles, including copper peroxide (CuO₂), calcium peroxide (CaO₂), magnesium peroxide (MgO₂), zinc peroxide (ZnO₂), barium peroxide (BaO₂), and titanium peroxide (TiOx) nanosystems. These nanosystems, characterized by their greater potential and treatment efficiency, are primarily needed in nanomedicine to combat various harmful pathogens. Researchers have extensively studied the effects of these peroxides in various treatments, such as catalytic nanotherapeutics, photodynamic therapy, radiation therapy, and some combination therapies. The tumor microenvironment (TME) is particularly unique, making the impact of nanomedicine less effective or even null. The presence of high levels of reactive oxygen species (ROS), hypoxia, low pH, and high glutathione levels makes them competitive against nanomedicine. Controlling the TME is a promising approach to combating cancer. Results: Metal peroxides with low biodegradability, toxicity, and side effects could reduce their effectiveness in treating the TME. It is important to consider the distribution of metal peroxides to effectively target cancer cells while avoiding harm to nearby normal cells. As a result, modifying the surface of metal peroxides is a key strategy to enhance their delivery to the TME, thereby improving their therapeutic benefits. Conclusions: This review discussed the various aspects of the TME and the importance of modifying the surface of metal peroxides to enhance their therapeutic advantages against cancer, as well as address safety concerns. Additionally, this review covered the current challenges in translating basic research findings into clinical applications of therapies based on metal peroxide nanoparticles.