Melanin-like nanoparticles as a potential novel therapeutic approach in ADPKD

Abstract

In this issue of EMBO Molecular Medicine, Sun and colleagues report the development of a novel therapeutic approach, and preclinical proof-of-concept evidence of its efficacy, for Autosomal Dominant Polycystic Kidney Disease (ADPKD) (Sun et al, 2024).

Figure 1. Schematic overview of the cellular effects of ultra-small melanin-like nanoparticles in PKD.

Renal epithelial cells lacking PC1 expression show energy and metabolic rewiring, accompanied by mitochondrial fragmentation and increased reactive oxygen species (ROS) production. In parallel, aberrant cytoplasmic Ca²⁺ levels result in increased cAMP. High cAMP activates PKA, which in turn activates cyclic AMP-responsive element-binding protein (CREB). Therapeutic approaches targeting cAMP have been developed and resulted in improvement in disease progression, with Tolvaptan being the first approved treatment. A study in the current issue of EMBO Mol Med shows that ultra-small Mn²⁺-chelated melanin-like nanoparticles, incorporating polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG) (MMPPs, for short), exert dual activity: scavenging mitochondrial ROS, and inhibiting CREB transcriptional activity by preventing DNA binding. Based on this dual action, treatment with MMPPs delays the progression of cyst growth in the kidney and liver in a PKD mouse model.