pH-responsive Fmoc-FF nanogels entrap internalized cargo within endosomes, preventing its trafficking to lysosomes

: Nanocarriers have become central tools in modern nanomedicine, enabling the intracellular delivery of therapeutic molecules that would otherwise be rapidly degraded or poorly internalized. Most nanocarriers internalized by endocytosis are sorted to the lysosomes, where acidification and enzymatic activity restrict bioavailability of their cargo. Trapping cargo in a pre-lysosomal compartment might result beneficial for successful intracellular delivery. Fmoc-FF nanogels are supramolecularly assembled, tunable carriers whose behavior responds to changes in the local chemical environment. Here, we characterize their intracellular trafficking and show that Fmoc-FF nanogels enter cells predominantly through caveolae-mediated endocytosis and accumulate within EEA1-positive early endosomes. Unlike conventional polymeric nanoparticles, these nanogels do not progress toward lysosomes. Instead, Fmoc-FF nanogels are associated with impaired early endosomal maturation, pronounced vesicle enlargement, and membrane destabilization. Acridine orange redistribution confirms loss of endosomal structure. In vitro data suggest that endosomal pH might drive structural rearrangement of the nanogel. Together, our findings demonstrate that Fmoc-FF nanogels profoundly remodel the endosomal network, altering endosomal trafficking and cargo processing, and highlight their potential as intracellular delivery platforms.