Thermo-responsive mucoadhesive in-situ gelling system loaded with surface-engineered PLGA nanoparticles for sustained intravaginal delivery of efavirenz in HIV pre-exposure prophylaxis.

HIV remains incurable, severely compromising the immune system. This study presents a surface-engineered, biocompatible nanoparticle-in-gel system for localized intravaginal delivery of Efavirenz (EFZ) in HIV PrEP. EFZ, a BCS Class II NNRTI, was efficiently encapsulated into Pluronic F-127 coated PLGA (50:50) nanoparticles (EFZ-PLGA NPs) using a modified emulsion solvent evaporation method optimized employing Box-Behnken design. Optimization of the process resulted in EFZ-PLGA NPs with an average size of 144.3 ± 2.13 nm, ζ-potential of -17.52 ± 0.78 mV, PDI of 0.248 ± 0.14 and entrapment efficiency of 87.00 ± 1.37 %. The surface energy (87.4 ± 1.17mN/m) indicated enhanced wettability, which would favour bioadhesion. AFM and SEM confirmed smooth, discrete and spherical shape of NPs while FTIR confirmed the chemical integrity of drug in NPs. DSC, and PXRD confirmed the amorphous state of FEZ in the polymer matrix. The nanoparticle-loaded gel displayed sol-gel transition at 38 ± 2.2 °C, gelation in 57 ± 2.1sec, viscosity of 13,857 ± 172.75 mPa·s (37 ± 0.5 °C) and sustained release (69.21 ± 2.38 % in 12 hrs). MTT assay indicated the reduced cytotoxicity of NPs. Pharmacokinetics revealed significantly (P < 0.0001) higher vaginal EFZ levels (Cmax: 18,309 ± 475 ng/mL) than that noted in plasma (Cmax: 59.7 ± 6 ng/mL), with 3-fold higher concentration in lower uterus (110.41 ± 7.98 ng/mL) as compared to upper (33.26 ± 3.82 ng/mL) and middle (25.23 ± 9.65 ng/mL) uterus, that exceeded the IC50 of EFZ (∼0.442-0.82 ng/mL). Histopathology confirmed biocompatibility, and safety of intravaginal formulations. This study demonstrates strong translational potential of the nanoparticle-in-gel platform that enables localized, sustained delivery of EFZ for intravaginal HIV PrEP. The favourable pharmacokinetics, safety profile, and bioadhesive properties of the drug delivery platform highlight its promise for clinical advancement in female-controlled HIV prevention strategies.