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We explored the use of new drug-loaded nanocarriers and their targeted delivery to the kidney glomerulus and in particular to podocytes, in order to overcome the failure of current therapeutic regimens in patients with proteinuric (i.e. abnormal amount of proteins in the urine) diseases. Podocytes are glomerular cells which are mainly responsible for glomerular filtration and are primarily or secondarily involved in chronic kidney diseases. Therefore, the possibility to utilise a podocyte-targeted drug delivery could represent a major breakthrough in kidney disease research, particularly in terms of dosage reduction and elimination of systemic side effects of current therapies. Four-arm star-shaped polymers, with/without a hydrophobic poly-ε-caprolactone core and a brush-like polyethylene glycol (PEG) hydrophilic shell, were synthesised by controlled/living polymerisation (ROP and ATRP) to allow the formation of stable ultrasmall colloidal nanomaterials of tuneable size (5–30 nm), which are able to cross the glomerular filtration barrier (GFB). The effects of these nanomaterials on glomerular cells were evaluated in vitro. Nanomaterial accumulation and permeability in the kidney glomerulus were also assessed in mice under physiological and pathological conditions. Drug (dexamethasone) encapsulation was performed in order to test loading capacity, release kinetics, and podocyte repairing effects. The marked efficacy of these drug-loaded nanocarriers in repairing damaged podocytes may pave the way for developing a cell-targeted administration of new and traditional drugs, increasing efficacy and limiting side effects.