The extracellular matrix (ECM) is a meshwork of proteins, mainly collagens, essential for tissue structure and functionality. Targeting ECM properties is a therapeutic approach with vast clinical potential[1]. Reactive oxygen species (ROS) are interesting candidate for that purpose. In this perspective, photodynamic therapy (PDT), used clinically for dermatological, ophthalmological and oncological applications, seems particularly promising. PDT is a photochemical therapeutic modality using photoexcitable agents (photosensitizers) and light to spatio-temporally generate toxic ROS at the site of irradiation. The majority of photosensitizers tend to form aggregates by π-π stacking in aqueous environment because of low water solubility, which strongly decreases their ROS-production efficiency. The main strategy to overcome this concern is to encapsulate the photosensitizers in nanovectors, especially polymer self-assembled micelles of poly(ethylene oxide)-block-poly(ε-caprolactone) PEO-PCL (5000-4000 g.mol-1) in our group[2,3]. The objective of our work was to identify the biological pathways that are transiently or permanently impacted by sublethal (meaning non-lethal) PDT based on free or encapsulated in PEO-PCL micelles pheophorbide at the human skin level. Thus, we used classical biochemical analyses and transcriptomics / proteomics on human dermal substitutes to analyze the different key parameters ensuring the dynamic remodeling of the extracellular matrix in response to free or encapsulated sub-lethal PDT. [1]Bonnans et al, Remodelling the extracellular matrix in development and disease, Nat Rev Mol Cell Biol 15 (2014) 786–801 [2]Gibot et al, Polymeric Micelles Encapsulating Photosensitizer: Structure/Photodynamic Therapy Efficiency Relation, Biomacromolecules 15 (2014) 1443–1455 [3]Zheng et al, Terahertz Spectroscopy Sheds Light on Real-Time Exchange Kinetics Occurring through Plasma Membrane during Photodynamic Therapy Treatment, Advanced Science 10 (2023) 2300589