Brain-targeted drug delivery using nanovesicles equipped with brain-targeting ligands is a promising approach to overcome the blood-brain barrier (BBB) and deliver therapies specifically to brain cells. Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by the loss of brain cells and pose significant challenges in treatment due to the BBB's restrictive nature. Targeting ligands, including peptides, proteins, aptamers, small molecules, and antibodies, can be incorporated into lipid-based and polymeric nanoparticles to enhance BBB penetration and direct therapies to specific brain cells, such as neurons, astrocytes, oligodendrocytes, microglia, neural stem cells, and endothelial cells of the BBB. These ligands improve the accumulation of nanoparticles in target cells while reducing off-target effects and systemic toxicity. However, some nanoparticles accumulate in peripheral organs, indicating the need for further optimization to enhance brain targeting. The review highlights various targeting ligands, such as transferrin, insulin, and choline, which have shown improved brain delivery when conjugated to nanoparticles. Additionally, strategies like receptor-mediated transcytosis and temporary BBB disruption using biochemical or physical methods are being explored. The use of specific receptors, such as the transferrin receptor (TfR) and low-density lipoprotein receptor (LDLR), has been effective in targeting brain cells. For example, ApoE-conjugated nanoparticles successfully targeted neurons in mice. Similarly, Angiopep-2, a peptide targeting LDLR, enhanced brain delivery of chemotherapy drugs. Targeting ligands like CTX, which binds to matrix metalloproteinase 2 (MMP-2), have been used to deliver gene therapies to glioblastoma cells. In the context of brain tumors, ligands such as ACUPA and cRGD have been used to target glioma cells. For neurons, ligands like neurotensin and TrkB-targeting aptamers have been used to deliver therapeutic agents. CPPs, such as TAT and RVG-9r, have also been used to enhance nanoparticle delivery to the brain. Despite these advancements, challenges remain in achieving high specificity and minimizing off-target effects. The review emphasizes the importance of developing more specific targeting ligands and nanoparticles to improve brain targeting and reduce systemic toxicity.Brain-targeted drug delivery using nanovesicles equipped with brain-targeting ligands is a promising approach to overcome the blood-brain barrier (BBB) and deliver therapies specifically to brain cells. Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by the loss of brain cells and pose significant challenges in treatment due to the BBB's restrictive nature. Targeting ligands, including peptides, proteins, aptamers, small molecules, and antibodies, can be incorporated into lipid-based and polymeric nanoparticles to enhance BBB penetration and direct therapies to specific brain cells, such as neurons, astrocytes, oligodendrocytes, microglia, neural stem cells, and endothelial cells of the BBB. These ligands improve the accumulation of nanoparticles in target cells while reducing off-target effects and systemic toxicity. However, some nanoparticles accumulate in peripheral organs, indicating the need for further optimization to enhance brain targeting. The review highlights various targeting ligands, such as transferrin, insulin, and choline, which have shown improved brain delivery when conjugated to nanoparticles. Additionally, strategies like receptor-mediated transcytosis and temporary BBB disruption using biochemical or physical methods are being explored. The use of specific receptors, such as the transferrin receptor (TfR) and low-density lipoprotein receptor (LDLR), has been effective in targeting brain cells. For example, ApoE-conjugated nanoparticles successfully targeted neurons in mice. Similarly, Angiopep-2, a peptide targeting LDLR, enhanced brain delivery of chemotherapy drugs. Targeting ligands like CTX, which binds to matrix metalloproteinase 2 (MMP-2), have been used to deliver gene therapies to glioblastoma cells. In the context of brain tumors, ligands such as ACUPA and cRGD have been used to target glioma cells. For neurons, ligands like neurotensin and TrkB-targeting aptamers have been used to deliver therapeutic agents. CPPs, such as TAT and RVG-9r, have also been used to enhance nanoparticle delivery to the brain. Despite these advancements, challenges remain in achieving high specificity and minimizing off-target effects. The review emphasizes the importance of developing more specific targeting ligands and nanoparticles to improve brain targeting and reduce systemic toxicity.