The high prevalence and significant impact of osteoporosis make it a leading cause of disability and mortality among older individuals. Neural networks have been reported to have a crucial role in both the physiological and pathological progression of osteoporosis, suggesting neural modulation could be used as an underlying strategy to attenuate the progression of osteoporosis. In this study, we firstly identified the significant relationship between vagus nerve and bone remodeling through artificial intelligence (AI)-based knowledge mining. Subsequently, iron oxide nanoparticles were incorporated into injectable hydrogels (termed M-Gels), which were then directly injected to envelop a single vagus nerve in the left neck of rats to prolong the retention issue in peripheral tissues (up to 20 weeks). Magnetic vagus nerve stimulation (mVNS) showed a rapid response characteristic of vagus activation. Notably, the mVNS administered at 20 Hz twice daily for 15 min over 16 weeks effectively improved bone metabolism in vivo. Using AI, we discovered that gut microbiota is an underlying cause of this phenomenon. This innovative mVNS method demonstrated the correlation between the vagus nerve and bone remodeling, revealing promising potential for osteoporosis therapy by long term mVNS.

Superparamagnetic iron oxide (SPIO) nanoparticles play an important role in mediating precise and effective magnetic neuro-stimulation and can help overcome limitations related to penetration depth and spatial resolution. However, nanoparticles readily diffuse in vivo, decreasing the spatial resolution and activation efficiency. In this study, we employed a microfluidic means to fabricate injectable microhydrogels encapsulated with SPIO nanoparticles, which significantly improved the stability of nanoparticles, increased the magnetic properties, and reinforced the stimulation effectivity. The fabricated magnetic microhydrogels were highly uniform in size and sphericity, enabling minimally invasive injection into brain tissue. The long-term residency in the cortex up to 22 weeks and the safety of brain tissue were shown using a mouse model. In addition, we quantitatively determined the magneto-mechanical force yielded by only one magnetic microhydrogel using a video-based method. The force was found to be within 7–8 pN under 10 Hz magnetic stimulation by both theoretical simulation and experimental measurement. Lastly, electrophysiological measurement of brain slices showed that the magnetic microhydrogels offer significant advantages in terms of neural activation relative to dissociative SPIO nanoparticles. A universal strategy is thus offered for performing magnetic neuro-stimulation with an improved prospect for biomedical translation.