Gene-activated matrices as nanomedicine platforms for bone regeneration: Delivery, translation and patent landscape

Protein biologics are constrained in critical-size bone defects not by insufficient potency, but by rapid clearance and the inability to sustain therapeutic signaling at the repair site. Dose escalation does not overcome this pharmacokinetic limitation and instead increases the risk of ectopic bone formation, osteolysis, and soft tissue toxicity. Sustained, localized delivery, not higher dosing, is the unmet requirement. Gene-activated matrices (GAM) address this problem by integrating nucleic acid cargo and delivery vectors within an implantable scaffold, converting infiltrating host cells into local sources of regenerative signals. This review examines GAMs as nanomedicine platforms for bone regeneration, tracing their development from scaffold bioactivity and the limitation of protein biologics to nucleic acid-based delivery. We compare viral vectors, lipid nanoparticles, polymeric polyplexes, calcium phosphate nanoparticles, and scaffold-integrated systems across transduction efficiency, expression kinetics, immunogenicity, and bone-site retention. We then examine how scaffold composition, architecture, and fabrication govern vector retention, release, and substrate-mediated transfection. This review then evaluates nucleic acid cargo selection and coordinated osteogenic and angiogenic gene delivery, including pDNA, mRNA, siRNA, miRNA, and explores emerging multi-factor, stimuli-responsive, and CRISPR-based GAMs alongside their translational constraints. A distinct feature of this review is its claim-level patent analysis, which identifies substantial intellectual-property white space in GAM development. Despite strong preclinical evidence, no GAM platform has simultaneously achieved scalable manufacturing, regulatory readiness as a combination product, and validation in a human-scale bone defect model. Clinical translation will require coordinated optimization of vector-scaffold interactions, manufacturing scalability, safety, and clinically relevant validation.