From blueprint to build: Metal ions in peripheral nerve development and engineering regeneration

Peripheral nerve injury (PNI) poses a substantial global health burden, affecting over 20 million individuals annually with frequent suboptimal recovery and persistent disability. The inherent limitations of nerve autografts, such as donor site morbidity and limited supply, underscore the clinical importance of nerve guidance conduits (NGCs) as a promising alternative. Nonetheless, the efficacy of current NGCs remains limited by their inability to recapitulate the spatiotemporally precise molecular cues of the native regenerative microenvironment. Our network meta-analysis highlights a significant efficacy gap in current NGCs and underscores the urgent clinical need for novel bioactive strategies. Metal ions have emerged as pivotal therapeutic candidates, capable of orchestrating regeneration by reactivating developmental programs through their tunable release kinetics and pleiotropic effects. By integrating spatiotemporal metal ion dynamics with single-cell transcriptomic data, this review deciphers a conserved, cell-type-specific signaling axis that operates across both development and regeneration. The review further evaluates advanced tissue engineering platforms, ranging from biodegradable metals to functional polymers, coupled with innovative fabrication technologies that enable spatiotemporally controlled ion delivery. This synthesis culminates in a development-inspired engineering blueprint that proposes a paradigm shift from passive structural support to active, development-mimetic instruction, ultimately aiming to accelerate the clinical translation of metal ion-based therapies for PNI (Scheme 1).