This study aims to develop a novel combinational drug delivery system for Alzheimer's disease (AD) treatment, focusing on the intranasal delivery of rivastigmine and insulin. Rivastigmine, an acetylcholinesterase inhibitor, and insulin, a complementary therapeutic agent, are encapsulated within N,N,N-trimethyl chitosan (TMC) nanoparticles (NPs). The TMC-NPs were synthesized using the ion gelation method, with an optimized formulation achieving a zeta potential of +17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. In vitro and ex vivo studies demonstrated that the TMC-NPs significantly improved the transport efficiency of both drugs through the sheep nasal mucosa compared to drug solutions. The NPs showed transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, compared to 52% and 21% for the drug solutions, respectively. Additionally, histological analysis confirmed the biocompatibility of the TMC-NPs, with no significant toxicity observed in the nasal tissue. These findings highlight the potential of TMC-NPs as a promising approach for enhancing nasal transport efficiency and simultaneously delivering rivastigmine and insulin to the brain, offering a novel strategy for treating AD and other neurodegenerative conditions.This study aims to develop a novel combinational drug delivery system for Alzheimer's disease (AD) treatment, focusing on the intranasal delivery of rivastigmine and insulin. Rivastigmine, an acetylcholinesterase inhibitor, and insulin, a complementary therapeutic agent, are encapsulated within N,N,N-trimethyl chitosan (TMC) nanoparticles (NPs). The TMC-NPs were synthesized using the ion gelation method, with an optimized formulation achieving a zeta potential of +17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. In vitro and ex vivo studies demonstrated that the TMC-NPs significantly improved the transport efficiency of both drugs through the sheep nasal mucosa compared to drug solutions. The NPs showed transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, compared to 52% and 21% for the drug solutions, respectively. Additionally, histological analysis confirmed the biocompatibility of the TMC-NPs, with no significant toxicity observed in the nasal tissue. These findings highlight the potential of TMC-NPs as a promising approach for enhancing nasal transport efficiency and simultaneously delivering rivastigmine and insulin to the brain, offering a novel strategy for treating AD and other neurodegenerative conditions.