pH-Responsive Mucus-Penetrating Nanoparticles for Enhanced Cellular Internalization by Local Administration in Vaginal Tissue

Low mucus penetration ability and cellular uptake seriously
limit
the effectiveness of local vaginal drug administration because of
the rapid foreign particulate and pathogen removal property of the
mucus layer. Our previous work proved that nanoparticles with a highly
dense polyethylene glycol (PEG) coating can penetrate mucus rapidly
(mucus-penetrating nanoparticles, MPPs) and improve drug distribution
and retention at mucosal surfaces. However, the “stealth-effect”
of the PEG coating also restricts cellular uptake of MPPs. In this
work, we designed pH-responsive mucus-penetrating nanoparticles (pMPPs)
with hydrazone bonds as the linker to conjugate a dense PEG surface
coating, which enabled the pMPPs to rapidly penetrate through the
mucus layer. More importantly, the acidic environment of the vaginal
mucus induces slow shedding of the PEG layer, leading to a positive
charge exposure to facilitate cellular uptake. Overall, pMPPs demonstrate
potential as an effective delivery platform for the prophylactic and
therapeutic treatment of female reproductive diseases.