Subcellular Organelle-Targeted Drug Delivery of Photodynamic Therapy and Gas-Photodynamic Combination Therapy

Photodynamic therapy (PDT), as a clinically viable non-invasive modality for tumor treatment, is characterized by precise spatiotemporal control with minimal systemic toxicity. The therapeutic efficacy of PDT is critically contingent upon subcellular photosensitizer localization, attributable to the restricted diffusion radius of reactive oxygen species (ROS, 20-40 nm). Consequently, the development of organelle-targeted drug delivery systems constitutes an essential strategy for PDT optimization. Nevertheless, the clinical translation of PDT remains constrained by inherent physicochemical and pathophysiological barriers, even following targeting refinement. These constraints-predominantly limited tissue penetration depth (<1 cm) and hypoxia-mediated therapeutic resistance-have driven the development of combinatorial therapeutic approaches. Among emerging strategies, gas-enhanced PDT has gained prominence due to its bifunctional capacity to modulate tumor pathophysiology and potentiate photosensitizer activity. The application of biocompatible gaseous agents enhances therapeutic outcomes through enhanced tumoral drug accumulation, amplified ROS generation, tumor microenvironment modulation, and reversal of multidrug resistance mechanisms. This review systematically evaluates organelle-targeted PDT delivery mechanisms, advanced strategies for gas-PDT synergistic therapy, and spatiotemporally controlled gas prodrug platforms. Collectively, these approaches establish subcellular precision medicine as a transformative paradigm for tumor therapy.