Black phosphorus nanosheet-enabled ROS-adaptive core-shell microneedles orchestrate immunoredox remodeling and neurotrophic regeneration for facial nerve repair.

BACKGROUND

Facial nerve injury often results in persistent facial paralysis because the early oxidative and inflammatory microenvironment compromises subsequent neurotrophic repair. Existing therapies are limited by insufficient spatiotemporal control over antioxidative and neurotrophic interventions at the lesion site, leading to suboptimal regenerative outcomes. Black phosphorus nanosheets (BPNs) have emerged as promising nanotherapeutics owing to their strong ROS-scavenging capacity, immunomodulatory potential, and favorable biodegradability. However, strategies that integrate BPN-mediated microenvironment regulation with sustained neurotrophic stimulation for facial nerve repair remain largely unexplored. Here, we developed a ROS-adaptive core-shell microneedle nanoplatform that sequentially remodels the oxidative-inflammatory niche and subsequently promotes neurotrophic regeneration through staged delivery of BPNs and nerve growth factor (NGF).

RESULTS

The microneedle shell consisted of a dynamic hyaluronic acid-phenylboronic acid/poly(vinyl alcohol) network loaded with BPNs, while the GelMA hydrogel core served as a reservoir for sustained NGF release. Under ROS conditions, cleavage of boronate ester bonds accelerated shell degradation and promoted BPN release. The released nanosheets reduced intracellular ROS, were associated with NRF2/HO-1 antioxidant pathway activation and NF-κB inflammatory signaling suppression in macrophages, and promoted polarization toward a pro-regenerative M2-like phenotype. This immunoredox modulation reduced oxidative stress and inflammatory mediator expression while establishing a more permissive microenvironment for neural repair. Subsequently, controlled NGF release from the core enhanced TrkA/AKT/ERK signaling, promoting neuronal differentiation, neurite extension, and axonal regeneration. The platform also improved Schwann cell proliferation, migration, and neurotrophic secretion, supporting remyelination and axonal guidance. In a mouse facial nerve crush model, treatment with BPN/NGF core-shell microneedles reduced oxidative damage and inflammatory infiltration, improved myelin sheath integrity and nerve ultrastructure, and accelerated early functional recovery compared with blank or single-cargo microneedle treatments.

CONCLUSION

This study presents a BPN-enabled ROS-responsive microneedle nanoplatform that addresses stage-specific barriers in facial nerve repair by sequentially regulating immunoredox responses and stimulating neurotrophic signaling. These findings highlight a promising nanobiotechnology strategy for peripheral nerve regeneration and may provide a broadly applicable framework for ROS-associated tissue injuries.