A Universal Bio-Hybrid Nanoparticle Backpack Platform Endows Stem Cells with Microenvironmental Resilience and Sustained Paracrine Signaling.

The therapeutic potential of mesenchymal stem cells (MSCs) in regenerative medicine is frequently thwarted by hostile post-injury microenvironments characterized by oxidative stress, inflammation, and rapid clearance, which compromise cell survival and paracrine efficacy. Herein, we establish a universal bio-hybrid "stem cell backpack" platform designed to fundamentally overcome these bottlenecks through precise surface interface engineering. By tethering drug-loaded mesoporous silica nanoparticles onto the MSCs membrane via mild, biocompatible click chemistry, we create a programmable nanotherapeutic depot that endows host cells with dual, synergistic capabilities: (1) robust scavenging of reactive oxygen species (ROS) to ensure cellular resilience and (2) sustained, localized release of regenerative factors to amplify paracrine signaling. Using corneal chemical injury as a rigorous proof-of-concept model, this platform demonstrated unprecedented regenerative potency. The engineered cells markedly outperformed conventional therapies by simultaneously suppressing inflammatory cascades, preventing fibrosis and neovascularization, and orchestrating multi-lineage regeneration, including epithelial restoration, nerve reinnervation, and limbal stem cell reactivation. Quantitatively, this approach achieved a 63.6% enhancement in transparency restoration and a 76.9% greater reduction in tissue defects compared to cell monotherapy. Crucially, the modular design of this backpack system allows for the interchangeable loading of diverse therapeutics, extending its applicability beyond ophthalmology to other tissues facing similar microenvironmental challenges. This work presents a transformative paradigm in nanomedicine, shifting the focus from passive cell delivery to active microenvironmental modulation, thereby offering a versatile and scalable strategy for next-generation regenerative therapies across diverse clinical indications.