Engineered microglia show promise in treating neurological diseases by modulating neuroinflammation and delivering therapeutics. Microglia, the brain's resident immune cells, play critical roles in maintaining homeostasis, synaptic pruning, and neurodevelopment. However, dysregulated microglial activity contributes to neurodegenerative and neuroautoimmune diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Re-engineering microglia through genetic modification or therapeutic modulation can alter their function to promote neuroprotection, reduce inflammation, and enhance repair. Genetic re-engineering involves altering microglial gene expression to deliver therapeutics, control neuroinflammation, or shift their phenotype. For example, engineered microglia expressing IL-15 or miR-155 can modulate the tumor microenvironment in glioblastoma, promoting anti-tumor responses. Similarly, microglia reprogrammed to express neurotrophin-3 (NT-3) or interleukin-4 (IL-4) have shown therapeutic potential in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), reducing inflammation and promoting remyelination. Microglia can also be used as delivery vehicles for drugs, such as paclitaxel, via phagocytosis or extracellular vesicles. Additionally, engineered microglia can be guided to target tumors or inflammatory sites using fluorescent markers or nanoparticles, improving surgical precision. However, challenges remain in ensuring targeted delivery, minimizing off-target effects, and overcoming barriers like the blood-brain barrier. Therapeutic modulation, which involves altering microglial gene expression without changing their genetic sequence, offers a reversible approach. This can be achieved through small molecules, RNA-based therapies, or nanoparticles that deliver therapeutic agents. Microglial receptors, such as RAGE and CD200R1, are key targets for modulating inflammation and neurodegeneration. For instance, blocking RAGE interactions with Aβ can reduce oxidative stress, while CD200R1 activation can suppress microglial activation. Future research aims to improve the efficiency and safety of engineered microglia, including optimizing genetic editing tools like CRISPR-Cas9, enhancing delivery systems, and understanding the functional differences between microglia and infiltrating macrophages. These advancements could lead to more effective treatments for a wide range of neurological diseases.Engineered microglia show promise in treating neurological diseases by modulating neuroinflammation and delivering therapeutics. Microglia, the brain's resident immune cells, play critical roles in maintaining homeostasis, synaptic pruning, and neurodevelopment. However, dysregulated microglial activity contributes to neurodegenerative and neuroautoimmune diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Re-engineering microglia through genetic modification or therapeutic modulation can alter their function to promote neuroprotection, reduce inflammation, and enhance repair. Genetic re-engineering involves altering microglial gene expression to deliver therapeutics, control neuroinflammation, or shift their phenotype. For example, engineered microglia expressing IL-15 or miR-155 can modulate the tumor microenvironment in glioblastoma, promoting anti-tumor responses. Similarly, microglia reprogrammed to express neurotrophin-3 (NT-3) or interleukin-4 (IL-4) have shown therapeutic potential in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), reducing inflammation and promoting remyelination. Microglia can also be used as delivery vehicles for drugs, such as paclitaxel, via phagocytosis or extracellular vesicles. Additionally, engineered microglia can be guided to target tumors or inflammatory sites using fluorescent markers or nanoparticles, improving surgical precision. However, challenges remain in ensuring targeted delivery, minimizing off-target effects, and overcoming barriers like the blood-brain barrier. Therapeutic modulation, which involves altering microglial gene expression without changing their genetic sequence, offers a reversible approach. This can be achieved through small molecules, RNA-based therapies, or nanoparticles that deliver therapeutic agents. Microglial receptors, such as RAGE and CD200R1, are key targets for modulating inflammation and neurodegeneration. For instance, blocking RAGE interactions with Aβ can reduce oxidative stress, while CD200R1 activation can suppress microglial activation. Future research aims to improve the efficiency and safety of engineered microglia, including optimizing genetic editing tools like CRISPR-Cas9, enhancing delivery systems, and understanding the functional differences between microglia and infiltrating macrophages. These advancements could lead to more effective treatments for a wide range of neurological diseases.