Chronic and hard-to-heal wounds remain burdensome because microbial contamination, dysregulated inflammation, and fragile tissue regeneration slow closure, while passive dressings often injure new tissue during removal. This review synthesizes polymer- and lipid-based nanostructures through a barrier-resolved lens that links composition, architecture, and processing to performance in protease- and salt-rich exudate across topical and transdermal routes. Quantitative trends include effective diameters of approximately 50–300 nm, practical constraints of sterile filtration at 0.2 μm, and therapeutic windows that prioritize contamination control on the first day, support proliferation around day three, and sustain remodeling beyond one week. Mechanistic evidence indicates that interfacial charge and the protein corona govern residence and uptake, lipid bilayers enable dual loading, degradable polymer matrices provide depot-like behavior, and hybrid constructs temper the early burst while improving storage stability.