pH-Responsive Self-Assembly of Renal-Clearable Nanoparticles in the Kidneys: One Assembly per Endosome.

Renal clearance is traditionally viewed as a passive filtration process governed by fenestrated glomerular capillaries. However, proximal tubular epithelial cells (PTECs) can still actively internalize, transform, and re-eliminate nanoparticles following glomerular filtration. Herein, we report that pH-responsive renal-clearable gold nanoparticles (AuNPs) of ∼2 nm in size can rapidly self-assemble into a single ∼180 nm nanosphere within individual PTEC endosomes in vivo once their isoelectric points (IEPs) overlapping the endocytic pH range (4.5-6.5), which has never been observed at the animal level. This pH-triggered one assembly per endosome delays subsequent reactive oxygen species (ROS)-mediated intracellular biotransformation into larger nanostructures while preserving membrane extrusion-based re-elimination. These findings reveal that endosomal acidity, alongside ROS, is a critical determinant of nanoparticle biotransformation and suggest that tailoring isoelectric points offers a route to control the subcellular assembly and clearance of renal-clearable nanomedicines at the animal level.