Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Theranostics

DOI: 10.7150/thno.136356