Type II diabetes mellitus (TIIDM) remains a globally challenging clinical issue for both dentists and orthopedists. Due to persistent hyperglycemia and altered host metabolism, the pathologic diabetic micromilieu with chronic inflammation and advanced glycation end products (AGEs) accumulation severely impairs bone regeneration efficiency [1,2]. In healthy physiological processes, stabilization and assembling of newly formed collagen fibers are primarily achieved by covalent intermolecular cross-link through enzymatic cross-links mediated by lysyl oxidase (LOX) [1,3,4]. For TIIDM, the excess accumulation of AGEs-mediated non-enzymatic cross-linking and down-regulate LOX, causes degradation of bone collagen degradation and further hinders the biomineralization process of bone regeneration [1,3]. Targeting “remodeling” of the pathologic diabetic micromilieu, we constructed the 3D-printed bio-scaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles (Sr-MBGNs) and gelatin methacrylate (GelMA). Sr-MBGNs act as the biomineralization precursor embedded in the GelMA simulated extracellular matrix, which releases Sr, Ca, and Si ions towards enhanced osteogenic properties. Satisfying bone formation could be obtained in the TIIDM model in vivo [5,6]. Based on the analysis through RNA-Seq and IHC, the innovative hint reveals that the nanocomposites could modulate extracellular matrix (ECM) reconstruction and simulate biomineralization through activating lysyl oxidase (LOX) to form healthy enzymatic crosslinked collagen, promoting cell focal adhesion, modulating the osteoblast differentiation, and boosting the release of non-collagenous proteins OCN (intrafibrillar mineralization dependent NCPs), thus orchestrating osteogenesis through Kindlin-2/PTH1R/OCN axis. This 3D printed bioscaffold is considered a multi-functional biomineralization-inspired working unit, which could remodel the “barren” diabetic micro-environment, thus, shedding light on the new illumination of bone regeneration for TIIDM.