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AbstractA major shortcoming in the treatment of mesangial cell-associated diseases such as IgA nephropathy, diabetic nephropathy, or lupus nephritis, which frequently progress to end-stage renal disease, is poor drug availability in the glomerular mesangium. Drug delivery via active targeting of nanoparticles, using ligands attached to the particle surface for target cell recognition to increase the biodistribution to the mesangium, is a promising strategy to overcome this hurdle. However, although several glomerular tissue targeting approaches have been described, so far no study has demonstrated the particles’ ability to deliver sufficient drug amounts combined with an appropriate nanoparticle target retention time to trigger relevant biological effects in the mesangium. In our study, we encapsulated erastin, a ferroptosis-inducing model compound, into adenovirus-mimetic, mesangial cell-targeting nanoparticles, enabling the direct visualisation of biological effects through ferroptosis-dependent histological changes. By intravital microscopy and analysis of histological sections, we were not only able to localise the injected particles over 10 days within the target cells but also to demonstrate biological activity in the renal glomeruli. In conclusion, we have characterised adenovirus-mimetic nanoparticles as a highly suitable drug delivery platform for the treatment of mesangial cell-associated diseases and additionally provided the basis for a potential renal disease model. [ABSTRACT FROM AUTHOR]