A paradigm shift from penetration: Material-based solutions for multidimensional spatiotemporal, hypoxic, and optical challenges in cutaneous photodynamic therapy

Despite considerable advancements in pharmaceutical strategies (e.g., nanocarriers, physical enhancement) to overcome the skin barrier for topical photodynamic therapy (PDT), clinical translation remains impeded by unresolved challenges. While previous reviews have predominantly focused on enhancing photosensitizer permeation, this work shifts the paradigm to systematically address three critical yet under-reviewed barriers: insufficient spatiotemporal precision in photosensitizer delivery, hypoxia-induced therapeutic resistance, and inefficient photon utilization. This review critically evaluated the transformative evolution from conventional formulations toward "smart" therapeutic architectures, presenting a coherent framework of material-based solutions engineered to overcome these specific challenges: (1) depth-resolved, stimuli-responsive, and molecular-targeted release mechanisms; (2) transdermal oxygen self-replenishing systems (e.g., catalase-mimetic nanomaterials or perfluorocarbon-based reservoirs); and (3) synergistic optical components to enhance photon utilization, including tissue optical clearing agents, light-guiding channels, and multifunctional light-responsive platforms. These integrated strategies enable the dynamic synchronization of photosensitizer bioavailability with pathological microenvironmental demands, allowing precise modulation across spatial, temporal, and dosage dimensions. Furthermore, we incorporated an analysis of commercially available and clinically investigated photosensitizers, providing critical context for the current state and future trajectory of the field. By bridging interdisciplinary insights from materials science, drug delivery, and photobiology, this work outlines a transformative roadmap for next-generation, precision-based dermatological therapies, marking a clear departure from penetration-centric approaches.