PurposeThe aim of this research work was to develop a mucoadhesive oro-gel–containing resveratrol loaded folate conjugated chitosan-lipidic nanoparticles (RES-FA-LP-NPs) for targeted delivery to oral squamous cell carcinoma (OSCC).MethodRES-FA-LP-NPs were prepared by hot homogenization followed by the ionic gelation method and were further incorporated in Carbopol® 971P gel. The in vitro cytotoxicity was assessed on folate receptor positive KB cell lines. The binding affinity of the folic acid (FA) ligand with the folate receptor was studied using Schrödinger, LLC, New York, NY, 2021.ResultsThe optimized unconjugated nanoparticles exhibited an average particle size of 107.5 nm ± 10.7 nm, polydispersity index (PDI) of 0.241 ± 0.024, zeta potential of 28.7 mV ± 0.9 mV, and encapsulation efficiency of 60 ± 3%. Surface folate conjugation of the nanoparticles increased the particle size to 149.9 nm ± 13.4 nm with PDI of 0.275 ± 0.041 and zeta-potential of 29.4 mV ± 1.4 mV. The RES-FA-LP-NP-loaded mucoadhesive oro-gel was found to have excellent mucoadhesive properties. The cumulative release from ex vivo diffusion studies on goat buccal mucosa at pH 6.8 was about 48.755 ± 8.627% and 64.802 ± 1.305% of resveratrol and folic acid respectively at the end of 8 h. The results of the cell culture study suggests that the developed RES-FA-LP-NPs were able to arrest OSCC (IC50 61.51 ± 2.70 μM/ml) at G0/G1 growth phase (58.08% apoptosis) of cell division. The binding interactions revealed that the ligand had excellent shape complementarity and a high binding affinity towards folate receptors.ConclusionPreliminary results state that the developed RES-FA-LP-NP-loaded gel can serve as a promising drug delivery system for the management of OSCC; however, more detailed investigations are needed to support the hypothesis.Graphical Abstract