A nanoengineered MSC therapeutic for synergistic therapy of lupus nephritis via cfDNA clearance and targeted immunomodulation.

RATIONALE: Lupus nephritis (LN) remains a clinical challenge due to the dose-limiting toxicity of conventional immunosuppressants and the poor engraftment/efficacy of mesenchymal stromal cell (MSC) therapies.

METHODS

We report a novel nanoengineered MSC therapeutic for LN by engineering MSCs with a cell-free DNA (cfDNA)-targeting dendritic nanogel. To obtain the hybrid MSC-G3K@T system, we coupled tacrolimus-loaded, disulfide-crosslinked polylysine dendrimer nanogels (G3K@T) onto the MSC membrane. Our system exploits two synergistic targeting strategies: the innate homing capacity of MSCs, plus the specific affinity of the cationic G3K dendrimer for anionic cfDNA, which enriches in inflamed kidneys.

RESULTS

Our system acts through two coordinated actions: the nanogel responds to the oxidative renal microenvironment and releases tacrolimus in a spatiotemporally controlled manner, thereby suppressing T-cell activation. At the same time, it scavenges cfDNA, blocking TLR-mediated pro-inflammatory signaling. Working together with the inherent immunomodulatory functions of MSCs, this dual-action strategy yielded robust efficacy in MRL/lpr mice, including a significant reversal of T-cell dysregulation, restoration of glomerular integrity, and reduction of proteinuria and IgG deposition.

CONCLUSIONS

We propose that MSC-G3K@T offers a promising route to augment cell-based therapies, creating a versatile platform that could be used to treat autoimmune and inflammatory diseases.