Multimodal nanoengineered scaffolds as regenerative microenvironment orchestrators: coupling mechanical, bioelectrical, immunological, and spatiotemporal therapeutic cues

Nanoengineered scaffolds are evolving from passive structural supports into instructive platforms capable of regulating the regenerative microenvironment. This narrative review examines how mechanical, bioelectrical, immunological, and spatiotemporal therapeutic cues are engineered and integrated within multimodal scaffolds. A literature search was performed using PubMed, Web of Science, Scopus, and Google Scholar databases for publications from January 2015 to March 2026, with earlier studies included when mechanistically essential. Mechanically instructive architectures regulate cellular organization and mechanotransduction, while conductive matrices enable electrical signaling. Immunomodulatory scaffolds reshape inflammatory pathways and immune-stromal communication, whereas micro/nanocarrier-based systems provide controlled therapeutic delivery through sustained, triggered, and programmed release strategies. Particular emphasis is placed on multimodal platforms involving mechanical-therapeutic, mechanical-bioelectrical, immunological-regenerative, and bioelectrical-immune/vascular interactions. Current evidence supports functional complementarity more consistently than true mechanistic synergy because individual contributions remain difficult to isolate. Translation is limited by long-term safety, manufacturing complexity, and lack of standardization. Future advances will require adaptive and sensing-enabled systems that coordinate regenerative cues while maintaining clinical feasibility. This framework reframes scaffold design from feature accumulation toward microenvironmental orchestration during regeneration.