Osteoimmune Regulating Nanomaterials for Bone Tissue Regeneration

Bone defects, particularly those associated with aging, osteoporosis, trauma, and tumor resection, remain a major global clinical challenge. Although nanomaterials have emerged as promising candidates for bone regeneration due to their tunable physicochemical properties, their clinical efficacy is still limited by a poor understanding of osteoimmunology, especially how nanomaterials regulate macrophage-mediated immune responses. Macrophages are central coordinators of inflammation resolution, osteogenesis, and angiogenesis, and their phenotype transition from proinflammatory M1 to pro-regenerative M2 is essential for successful healing. However, most nanomaterials are rapidly phagocytosed upon implantation, leading to unintentional immune activation and diminished therapeutic efficiency. Therefore, unraveling how nanomaterials modulate macrophage behavior, through both intracellular signaling and early membrane interactions, is critical for developing next-generation osteoimmunomodulatory biomaterials.

This thesis aims to design mesoporous silica-based nanomaterials (MSNs) with defined immunomodulatory functions, elucidate the cellular and molecular mechanisms underlying nanomaterial-mediated osteoimmunoregulation, and explore their translational potential for bone regeneration. Specifically, this work investigates two complementary regulatory pathways: (1) autophagy-mediated immunomodulation, where MSNs deliver autophagy-inducing agents to reprogram macrophage phenotype, and (2) membrane-contact–mediated immunomodulation, where MSN surface topology directly influences macrophage membrane receptor organization and early immune signaling.

First, we summarized recent advances in porous nanomaterials for bone repair, highlighting autophagy as a pivotal regulator linking immune response and osteogenesis. Building on these insights, rapamycin-loaded MSNs were engineered to enhance intracellular autophagy activation. These nanocarriers successfully promoted M2 polarization, suppressed proinflammatory cytokine secretion, and significantly enhanced osteogenesis in vitro and in vivo, demonstrating the therapeutic advantage of autophagy-mediated osteoimmunomodulation.

Second, we developed neodymium-doped MSNs to investigate whether bioactive rare-earth elements could synergistically modulate autophagy and macrophage phenotype. The nanoparticles activated macrophage autophagy, reduced inflammation-induced osteolysis, and promoted bone regeneration, while MSN-based delivery minimized toxicity typically associated with free neodymium compounds. These findings broaden the spectrum of functional dopants applicable for osteoimmunoregulatory biomaterial design.

Third, we explored a distinct immunoregulatory mechanism mediated by early nanomaterial-cell membrane interactions. MSNs with pollen-like surface topography were synthesized to probe how nanoscale roughness influences macrophage behavior prior to particle internalization. We found that surface morphology altered membrane receptor clustering, reshaped downstream signaling pathways, and guided macrophage phenotype and cytokine secretion, ultimately enhancing bone regeneration. This work reveals membrane-contact signaling as an underappreciated but powerful lever for osteoimmune engineering.

Collectively, the studies presented in this thesis provide mechanistic insights and practical design strategies for engineering osteoimmunomodulatory nanomaterials. By integrating autophagy regulation, surface-topography-mediated membrane signaling, and functional ion/drug delivery, this research advances the development of next-generation immuno-instructive biomaterials for bone tissue regeneration. These findings contribute to the broader field of osteoimmunology and may inspire new translational approaches for treating large bone defects, non-unions, and other skeletal disorders.