Neuroma formation following the repair of nerve injuries exceeding 0.9 cm in length severely impedes functional recovery. To overcome this challenge, we engineered magnetically responsive core-shell nanoparticles (MnFe 2 O 4 @ZIF-8@Retinoic acid, MFZR; 90–360 nm) to guide regeneration within a decellularized umbilical cord artery (DUCA) conduit. We investigated the synergistic effect of MFZR under an external magnetic field (MF) on Schwann cell behavior in vitro and on sciatic nerve repair in a rat model. Under MF exposure, MFZR significantly enhanced Schwann cell migration, alignment, and elongation on DUCA conduits. In-vivo , the MFZR+MF combination potently promoted functional recovery, as measured by the sciatic functional index, muscle compound action potential, and nerve conduction velocity, without inducing DUCA-related inflammation. Histological analysis demonstrated robust regeneration, characterized by increased axon diameter, an improved G-ratio, and elevated expression of S100 and NF-200. This regeneration was facilitated by a healing-promoting M2 macrophage polarization at the injury site. Critically, the strategy exhibited no systemic toxicity. These findings establish that magnetically guided MFZR effectively prevents neuroma in the DUCA conduits, orchestrates a pro-regenerative microenvironment, and achieves significant functional recovery, offering a promising translatable strategy for nerve repair.
Background Mn 2+ -mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO 3 − level in the system. Although the physiological buffers (H 2 CO 3 /HCO 3 − ) provide certain amounts of HCO 3 − , the acidity of the tumor microenvironment (TME) would seriously affect the HCO 3 − ionic equilibrium (H 2 CO 3 ⇌ H + + HCO 3 − ). As a result, HCO 3 − level in the tumor region is actually insufficient to support effective Mn 2+ -mediated CDT. Results In this study, a robust nanomodulator MnFe 2 O 4 @ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO 3 − is presented to enhance therapeutic efficacy of Mn 2+ -mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO 3 − ionic equilibrium to the positive direction, significantly boosting the generation of the HCO 3 − . Most importantly, such HCO 3 − supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe 2 O 4 of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions This work addresses the challenge of insufficient HCO 3 − in the TME for Mn 2+ -mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn 2+ -mediated CDT agents to treat cancer effectively.
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