Monoclonal antibodies (mAbs) are lab-engineered, Y-shaped protein structures³⁶ composed of two heavy and two light chains. The variable region (Fab) at the ends binds to the target antigen³⁷, while the constant region (Fc) interacts with immune-cell receptors³⁸. The binding of mAbs to Aβ—in its soluble or plaque form—activates immune processes such as phagocytosis via Fc receptors on microglia, thereby facilitating plaque removal. Complement receptors also enhance clearance through the complement cascade³⁹⁴⁰. Although effective in promoting Aβ clearance, mAbs may induce inflammation through activation of Toll-like receptors (TLRs)⁴¹⁴². Drugs such as aducanumab exploit this mechanism to target Aβ and trigger microglial activation for plaque clearance, though their effects can be complex and require careful management⁴³. Amyloid-related imaging abnormalities are serious side-effects of anti-Aβ antibodies (e.g., aducanumab, lecanemab, gantenerumab). Edema (ARIA-E) and hemosiderin-related hemorrhages (ARIA-H) are associated with disruption of the blood–brain barrier following amyloid clearance from cerebral vessels⁴⁴. APOE-ε4 carriers face an increased risk. Symptoms include headaches, confusion, and seizures. Regular MRI monitoring is required for early detection, and dose adjustments may be necessary in severe cases⁴⁵.

Therapies that target tau tangles modulate several receptors and molecular partners. One key target is the microtubule-associated protein tau⁶⁵. Glycogen synthase kinase-3 (GSK-3) inhibitors and mitogen-activated protein kinase (MAPK) inhibitors both reduce tau phosphorylation⁶⁶. Because MAPKs mediate stress- and inflammation-related signaling, their down-regulation lessens phosphorylation and inflammation. These interactions decrease tau aggregation, stabilize microtubules, and reduce tau-induced neurotoxicity, thereby helping to maintain neuronal function and limiting tau’s prion-like propagation⁶⁷.

• Tau-aggregation inhibitor TRx0237 (LMTX) dissolves existing tangles and may halt or reverse dementia progression⁹⁹.

• Neuroinflammation modulators such as sargramostim reduce immune dysregulation and may improve cognition; mefenamic acid is under study for similar effects¹⁰⁰.

• NLRP3-inflammasome inhibitors (e.g., MCC950, tetramethylpyrazine, kakonein) decrease neuroinflammation in preclinical AD models^101102103.

• β-Site amyloid precursor-protein cleaving enzyme-1 (BACE1) inhibitors (verubecestat, lanabecestat) lower Aβ synthesis by inhibiting β-secretase¹⁰⁴. However, many agents (e.g., NB-360) were halted owing to adverse effects such as hair depigmentation, anxiety, weight loss, falls, suicidality, and sleep disorders. Umibecestat (CNP520) advanced further because of higher selectivity and favorable pharmacokinetics, yet overall risks highlight the difficulty of targeting amyloid pathways¹⁰⁵¹⁰⁶.

Polymeric Nanoparticles: Polymeric nanoparticles have been found to be useful for penetrating the blood–brain barrier (BBB) and releasing drugs at the target, i.e., Aβ plaques¹⁰⁷¹⁰⁸. Experiments have also shown that these nanoparticles can be functionalized with targeting ligands that increase their selectivity toward Aβ and therefore enhance the efficacy of drug delivery and decrease the amyloid load in the brain¹⁰⁹¹¹⁰.

Lipid Nanoparticles: Lipid nanoparticles have potential in the encapsulation and distribution of therapeutic agents that deal with Aβ and tau aggregates¹¹¹¹¹². These systems offer long-term stability and controlled release, can cross the BBB, and may reduce neurotoxicity while improving cognitive function¹¹³.

Exosome Engineering: Small interfering RNAs and other small molecules can be incorporated into exosomes, naturally occurring vesicles 40–100 nm in size, to target neurons¹¹⁴. Exosomes can enter the brain and release their contents, specifically near Aβ plaques and tau tangles¹¹⁵.

Exosome-Loaded Drug Carriers: Exosomes combined with other delivery systems and nanoparticles can increase the specificity and efficiency of drug delivery. Preclinical studies of exosome-loaded nanoparticles have shown their potential to target Aβ and tau tangles¹¹⁶¹¹⁷.

Peptide-Conjugated Nanoparticles: Nanoparticles can be functionalized with high-affinity peptides that specifically bind Aβ plaques and tau tangles, resulting in enhanced targeting efficiency¹¹⁸. For therapeutic applications, these peptide-conjugated nanoparticles can effectively transport active agents, including antibodies and small molecules, to pathological regions to improve treatment outcomes and minimize adverse effects¹¹⁹¹²⁰.

Cell-Penetrating Peptides (CPPs): CPPs are used to carry therapeutically valuable agents across cell membranes¹²¹. CPPs can be coupled with a drug or genetic material to improve their uptake by neurons, thereby directly targeting Aβ and tau damage and possibly even altering the disease course¹²².

Immunoliposomes: Immunoliposomes, which are liposomes linked with particular antibodies against Aβ or tau, have been created to enhance drug-delivery selectivity and effectiveness¹²³. The BBB permits only regulated entry of substances, posing a major challenge to delivering Alzheimer’s-disease therapeutics into the brain. For large molecules like monoclonal antibodies (e.g., aducanumab), transport is restricted, and this requires an intravenous infusion or specialized methods of delivery. Small-molecule drugs generally have either low bioavailability or rapid clearance. Possible strategies include nanoparticle-based delivery, receptor-mediated transcytosis, and focused ultrasound for temporary opening of the BBB to maximize therapeutic effects and minimize systemic side effects. These systems can cross the BBB and thus provide ligands to affected regions; consequently, they have demonstrated their ability to reduce amyloid and tau accumulation in preclinical trials¹²⁴¹²⁵.

Multifunctional Liposomes: Liposomes with targeting ligands, imaging agents, and therapeutic agents are useful in the management of multiple aspects of this disease¹²⁶. Liposomes can deliver and release drugs, monitor the response and effectiveness of treatment, and respond accurately to Aβ and tau tangles¹²⁷¹²⁸.

• Blood–Brain Barrier (BBB) Permeability: The BBB remains a major obstacle, limiting the ability of therapeutic agents (especially large molecules and biologics) to reach effective concentrations in the brain parenchyma. At the molecular level, this barrier limits transcytosis and receptor-mediated transport unless specific ligands or transport mechanisms are exploited¹²⁹.

• Rapid Systemic Clearance: Nanoparticles, liposomes, and other delivery vehicles are often rapidly cleared by the reticuloendothelial system (RES), leading to reduced circulation time and poor central nervous system (CNS) bioavailability. This clearance depends on molecular surface features such as charge and hydrophilicity, which can reduce systemic circulation and CNS accumulation¹³⁰.

• Immunogenicity and Biocompatibility: Synthetic carriers are recognized as foreign particles by the immune system, which may trigger inflammatory responses, immune clearance, or allergic reactions. Minor changes in surface chemistry at the molecular level (e.g., terminal groups, PEG density) can dramatically affect immune recognition¹³¹.

• Inconsistent Physicochemical Properties: Variability in nanoparticle synthesis can lead to differences in size, surface charge, and morphology, affecting drug-loading efficiency, release kinetics, and targeting accuracy. Batch-to-batch variability in nanoparticle synthesis (e.g., inconsistent nucleation or polymerization rates) can alter critical parameters like zeta potential, hydrodynamic diameter, and surface-ligand density, which influence molecular interactions with the BBB and target cells¹³².

• Potential toxicity of carriers: Some carrier materials or their degradation products (e.g., cationic polymers, metal-based NPs) may generate reactive oxygen species (ROS) or interfere with cellular organelles and enzymes, leading to molecular-level toxicity¹³³.

• Enzymatic degradation of peptides: Therapeutic peptides are highly susceptible to proteolytic enzymes (e.g., peptidases, endopeptidases) in blood and tissues, leading to cleavage at specific amino-acid residues and a short systemic half-life. Structural modification (e.g., D-amino acids, PEGylation) is often needed to enhance stability¹³⁴.

• Cell-Penetrating Peptides: CPPs like TAT allow drug entry via direct translocation or endocytosis, but they lack receptor specificity and are prone to enzymatic cleavage. Modifying CPPs with drugs can change their conformation, reducing efficiency and stability at the molecular level¹³⁵.

• Exosome Production Challenges: Exosomes—natural nanocarriers—are heterogeneous in composition (lipids, proteins, RNA). Isolating them in a reproducible, scalable, and clinical-grade manner requires controlling the molecular makeup, including tetraspanins (e.g., CD63, CD81) and surface markers, which is technically difficult¹³⁶.

In addition to the points mentioned above, other challenges in drug delivery include cargo heterogeneity in exosomes, limited stability and shelf-life of formulations, weak correlation between pathology clearance and cognitive benefit, poor translational value of preclinical models, and uncertain long-term safety of novel delivery systems. Further research is required to overcome these challenges and enhance the efficacy of CNS-targeted therapies¹³⁷¹³⁸.