Osteoimmunomodulatory Stem Cell Nanoghosts as a Novel Nanotherapeutic for Bone Regeneration

Abstract

Critical-sized bone defects and implant-associated complications are often exacerbated by chronic inflammation, which compromises tissue repair and implant integration. Mesenchymal stromal cell (MSC)-derived extracellular vesicles have emerged as promising immunomodulatory nanotherapeutics; however, their clinical translation remains constrained by low yield, heterogeneity, and poor scalability. Here we present a bioengineered MSC-derived nanoghosts platform designed to overcome these translational barriers while enabling tunable osteoimmunomodulatory function. By coupling high-yield nanoghost fabrication with biomimetic MSC conditioning, we demonstrate that oxygen tension (5 or 21% O2) and 3D culture substrates (5 or 15 wt-% GelMA) can reprogram MSC immunophenotype. Nanoghosts generated under hypoxic and 3D conditions displayed enriched anti-inflammatory cargo, preserved MSC viability under inflammatory stress, and partially rescued osteogenic mineralization in the presence of pro-inflammatory cytokines. Together, these findings showcase MSC nanoghosts as scalable and bioactive immunoregulatory nanotherapeutic capable of modulating immune-bone crosstalk, providing a translational strategy to mitigate inflammation-driven impairment of bone regeneration and implant integration. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/724218v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@f965deorg.highwire.dtl.DTLVardef@18f007borg.highwire.dtl.DTLVardef@168a194org.highwire.dtl.DTLVardef@4818fe_HPS_FORMAT_FIGEXP M_FIG C_FIG