In situ self-growth nano-selenium-loaded engineered biomimetic bioparticles unleash potent trained immunity via metabolic and epigenetic reprogramming for superior antimicrobial defense

Bacterial infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), pose a growing global health threat due to antibiotic overuse and misuse. Although trained immunity is a promising strategy against MDR bacteria, multifunctional immunomodulatory biomaterials capable of inducing balanced trained immunity remain largely unexplored. Here, we developed an in situ self-grown nano-selenium-loaded bacterium-like particle (SeBLP) by a microbe-mimetic strategy harnessing in situ self-growth and a subsequent acidic stabilization treatment. This unique approach directly constructs a protein/nucleic acid-free architecture with speckled selenium nanoparticles on a probiotic scaffold, enabling straightforward fabrication, favourable biocompatibility, and multifunctionality. We found that SeBLP effectively scavenges DPPH and ABTS radicals, inhibits bacterial growth in vitro, and elicits rapid, broad-spectrum anti-infective activity in vivo. Importantly, SeBLP induces trained immunity by reprogramming metabolism and epigenetics via the GSH/ROS/mTOR and NF-κB pathway while maintaining redox homeostasis and inflammatory balance. Furthermore, a single immunization with SeBLP bound to an S. aureus multi-epitope antigen significantly enhances immune protection against MRSA and elicits a balanced Th1/Th2 response. Our study demonstrated that SeBLP is a microbe‐inspired multifunctional nano-selenium bioparticle capable of orchestrating balanced trained immunity and substantially enhancing antigen‐specific adaptive protection. These findings not only demonstrate a bioinspired strategy merging nanotechnology with probiotic scaffolds but also pave the way for innovative immunomodulatory therapies against MDR infections.