Neurodegenerative diseases require innovative therapies targeting autophagy dysfunction, neuroinflammation, and genetic defects. This chapter examines integrated neurotherapeutic strategies, including nanoparticle delivery, gene editing, and optogenetics, designed to cross biological barriers and correct disease mechanisms. Engineered nanoparticles can deliver autophagy enhancers and anti-inflammatory agents across the blood–brain barrier, whereas avian-associated virus-mediated TFEB overexpression can enhance lysosomal function and suppress inflammasomes. CRISPR corrects genetic defects, such as PARK2 for mitophagy restoration and C9ORF72 repeat excision to reduce toxic dipeptides. Moreover, optogenetics modulates microglial function through TMEM119-driven opsins, reducing neuroinflammation while preserving phagocytosis in neurodegenerative conditions. Challenges remain with nanoparticle endosomal entrapment, immunogenicity, CRISPR off-target effects, and optogenetic invasiveness. Emerging solutions include artificial intelligence-optimized blood–brain barrier carriers, sonogenetics, and miRNA-targeted vectors. This chapter outlines a translational framework, balancing molecular insights with clinical hurdles, advancing precision neurotherapeutics to modify disease progression.