rs-TAC PDC, a peptide drug-conjugate, for targeted delivery of tacrolimus and sericin alleviates podocyte injury in diabetic nephropathy

Despite intensive glucose control or blood pressure control, the remission of proteinuria in patients with diabetic nephropathy remains extremely low. Tacrolimus has been successful in treating immune-related and genetic-related nephropathy, providing a feasible method to reduce proteinuria and podocyte damage in patients with diabetic nephropathy. However, doctors do not know how to avoid the risk of increased blood glucose levels and infection induced by tacrolimus. Here, we developed a RLD-sericin-tacrolimus conjugate (rs-TAC PDC), that specifically targets delivery of tacrolimus and sericin to podocytes. Administration of the rs-TAC PDC increases the levels of tacrolimus and serine in podocyte, and alleviates podocyte damage and albuminuria in diabetic nephropathy mice, with a better th44erapeutic effect than tacrolimus or serine alone. Mechanistically, tacrolimus restores the podocyte cytoskeleton, and inhibits the IL17 signalling pathway, and sericin promotes endogenous H2S production and reduces oxidative stress. Both of tacrolimus and serine work synergistically to protect podocyte from damage. On the other hand, the rs-TAC PDC reduces the accumulation of tacrolimus in the pancreas, lymph nodes, and thymus, subsequently reducing the risk of exacerbating hyperglycaemia and infection. Overall, the rs-TAC PDC provides better therapeutic effects and fewer side effects than tacrolimus alone in the treatment of diabetic nephropathy. [Display omitted] •The rs-TAC PDC consists of RLD, sericin and tacrolimus.•The rs-TAC PDC increases intracellular tacrolimus and serine levels in podocytes.•The rs-TAC PDC alleviates podocyte damage with a better effect than tacrolimus or serine alone.•The rs-TAC PDC reduces accumulation of tacrolimus in the pancreas, lymph nodes, and thymus.•The rs-TAC PDC avoids exacerbating hyperglycaemia and infection in diabetic nephropathy mice compared to tacrolimus.