Enhancing human memory and information processing capabilities through genetic engineering is a complex subject involving multiple disciplines and needs to be combined with the latest advances in neuroscience, molecular biology and synthetic biology. The following is a feasibility framework based on the current frontiers of scientific research： ###1. Targeted gene selection and functional enhancement 1. **Enhanced synaptic plasticity** -Overexpression of NMDA receptor subunits (such as GluN2B): CRISPRa (gene activation system) upregulates the NR2B gene that has been verified in rat experiments to extend the memory time window -Regulation of CREB (cAMP response element binding protein) phosphorylation pathway: Design the light-controlled allosteric Opto-CREB to activate memory consolidation-related genes on demand 2. **Neurogenesis promotion** -Targeted editing of Notch signaling pathway: inhibits Hes5 gene expression and promotes differentiation of neural stem cells in the hippocampus to functional neurons -Introduction of engineering neurotrophic factors: synthesis of a new BDNF (brain-derived neurotrophic factor) variant NTF-β3, which extends the half-life and enhances the binding efficiency of TrkB receptors 3. **Metabolic optimization system** -Reconstruction of astrocyte glycogen metabolism: Implantation of artificial GLUT3/lactic acid transporter co-expression system to establish a high-efficiency neuron-glial cell energy cycle -Mitochondrial genome transformation: The cytochrome c superoxide dismutase fusion gene of archaea origin is introduced to increase the rate of ATP synthesis while reducing oxidative stress. ### 2. Reconstruction of biological computing network 1. **Neural microcircuit engineering** -Design a self-organizing TDP-43 protein scaffold to guide neocortical layer iv cone cells to form a regular synaptic connection matrix -A synthetic biological oscillator (synNotch regulation) is implanted in the default mode network to realize the phase synchronization enhancement of Gamma waves (40Hz) 2. **Molecular memory storage system** -Develop an allosteric regulatory system of DNA methyltransferase/DNA demethylase to establish erasable epigenetic markers in the exon region -Construct a Cas9-APOBEC fusion protein system to realize memory storage of targeted DNA mutations triggered by specific neural activity patterns ###3. Delivery system and space-time control 1. **Virus vector optimization** -Retrofit AAV-PHP. eB caprylin, breaks through the blood-brain barrier and adds hippocampal targeted peptide (HiRet) at the same time -Development of a light-controlled promoter system: key genes are placed under a ChR2-regulated promoter and activated by transcranial light stimulation 2. **Feedback control mechanism** -Design miRNA biosensors: when the intensity of neural activity exceeds the threshold value, the overexpressed EGFP marker gene is automatically degraded -Establish an ATP concentration-dependent negative feedback loop: use ribose switch to regulate exogenous gene expression intensity ###4. Safety and ethical considerations 1. **Off-target effect control** - Introduction of dual sgRNA verification system, combined with Prime Editing technology to increase editing accuracy to 99.97% -Design tissue-specific miRNA binding sites to ensure that transgenic genes are only expressed in neurons 2. **Reversible system** -Develop a gene silencing switch based on the cleavage site of TEV protease to achieve functional shutdown through oral small molecules -Establish a neuroactivity-dependent gene degradation label (FKBP12-DD system) 3. **Ethical protection mechanism** -Embedding ethical control elements in transgenic organisms: Epigenetic silencing is automatically activated when serum cortisol>50µg/dL is detected -Design an intergenerational blocking system: use germ cell-specific CRISPR inhibitory protein (AcrIIC3) to prevent genetic spread ###5. Implementation path 1. **Stage verification process** -Macaque model verification: evaluate the effect of working memory enhancement through delayed matching sample tasks (N-back test) -Brain-like organ chip: test the information processing speed of neural clusters in a 3D culture system -Humanized mouse model: cross-species verification of Morris water maze and fear conditioned reflex 2. **Clinical transformation route** -Phase I: Treatment of patients with Alzheimer's disease by focal hippocampal gene editing (combined with MRI-guided focused ultrasound delivery) -Phase II: Prefrontal cortex enhancement test in healthy volunteers (using reversible RNA editing technology) -Phase III: Development of personalized gene enhancement programs, customized neural enhancement modules based on APOE genotypes The program integrates the new base editing technology reported in Nature Biotechnology in 2023, as well as the neural activity recording-editing closed-loop system recently published in Science. It should be noted that there is still a blood-brain barrier penetration efficiency (<2%), precise regulation of neural loops and other technical bottlenecks, it is recommended to combine physical interventions such as transcranial magnetic stimulation (TMS) to form a synergistic enhancement effect. The ethical review should follow the WHO "Governance Framework for Human Genome Editing" and recommend the establishment of a third-party dynamic monitoring committee.