Barrier-Guided Local Nanopharmaceutics for Cartilage and Osteochondral Regeneration: From Effective Tissue Exposure to Cell-State Control and Translational Quality Attributes

Local nanopharmaceutic systems are increasingly used to prolong intra-articular residence, improve cartilage access, control local release, and regulate repair-relevant cell states. However, joint retention is often mistaken for effective tissue exposure, and nanoscale complexity is frequently treated as an advantage without demonstrating which transport, biological, or mechanical barrier it resolves. This narrative review develops a barrier-guided framework for nanocarriers, nano-enabled hydrogels, extracellular vesicles, and spatial osteochondral constructs. We distinguish nominal formulation identity from the delivered material state that emerges after dilution, protein adsorption, mechanical loading, and degradation, and we separate joint-cavity persistence, cartilage partitioning and penetration, and bioavailable cargo at target cells. The evidence is strongest when a controllable material attribute is linked to a depth-resolved exposure or repair function; it remains uneven for coupled loading–release behavior, direct cross-platform comparisons, and transferable acceptance limits. We therefore distinguish published quantitative anchors from product-specific specifications and propose a staged workflow that defines two-sided failure boundaries for size and dispersity, binding–dissociation kinetics, stress relaxation, dose, and potency. Across platforms, the practical priorities are reversible rather than maximal binding, matched static-versus-loaded release testing, mechanism-necessity controls for extracellular vesicles, modality-aware fate measurements, and critical quality attributes linked to in vivo performance. The most credible strategy is the minimum necessary complexity that preserves a measurable structure–property–exposure–function relationship from manufacture through remodeling.