Blood-brain barrier-penetrant pharmacological strategies for neuroinflammation in Alzheimer’s disease: small molecules and engineered peptides

Recognition of Alzheimer’s disease (AD) as a neuroinflammatory disorder, alongside amyloid-β and tau pathology, necessitates the development of innovative therapies capable of overcoming blood–brain barrier (BBB)-mediated limitations to brain drug delivery. This review discusses current efforts to develop BBB-permeable small molecules and peptide-based therapies targeting the neuroimmune modulators TREM2, the NLRP3 inflammasome, RIPK1, and the cGAS-STING signaling pathway, with consideration of the concept of the neurovascular paradox. Despite promising recent developments, the trade-off between permeability, selectivity, and cytotoxicity remains a significant issue. The current findings indicate that BBB penetration, the timing of microglial targeting, immunosuppressive effects, and neuroimmune homeostasis should be considered when seeking to modulate neuroinflammation effectively. Novel delivery systems, such as those using cell-penetrating peptide shuttles and antibody-based transport systems, may help address BBB limitations, and biomarker-guided treatment is increasingly important. Overall, this review reframes brain drug delivery not only as a function of pharmacokinetic parameters but also as part of a system integrating neurovascular physiology, neuroimmunology, and medicinal chemistry.