Innovations in Drug Delivery: Crossing the Blood-Brain Barrier with Aptamers

Aptamer platforms offer a translational route to overcome blood–brain barrier (BBB) constraints by enabling receptor‑mediated transcytosis, supporting targeted CNS delivery in preclinical and early translational studies.

Which receptor targets enable receptor‑mediated transcytosis? Aptamers directed at the transferrin receptor and low‑density lipoprotein (LDL) receptor family members use clathrin‑ or caveolin‑dependent uptake to cross the human BBB. Endothelial expression gradients and interspecies differences in receptor density modulate uptake efficiency and should inform translational model selection. Deliberate receptor choice therefore balances CNS targeting against peripheral off‑target uptake and defines shuttle capacity for different payloads.

Selection and design advances now sharpen aptamer affinity and BBB penetration. In vivo SELEX coupled with iterative screens enriches ligands that traffic across intact vasculature, while in silico optimization accelerates cycles and stabilizes predicted folds to improve affinity and specificity. Iterative in‑vivo selection reduces false positives from cell‑ or protein‑only screens, and computational design shortens lead timelines and improves structural stability—lifting overall candidate quality and speeding lead nomination.

Nanoparticle–aptamer hybrids extend circulation time and protect against nuclease degradation while enabling controlled CNS release. Key formulation strategies—PEGylation, backbone modifications (2′‑O‑methyl, locked nucleic acids [LNAs]), and conjugation to biodegradable nanoparticles—address stability and biodistribution concerns without overstating efficacy; these choices determine dosing windows and intracerebral exposure.

However, major challenges include rapid in vivo degradation (mitigated by chemical stabilization), intracellular entrapment after transcytosis (mitigated by endosomal‑escape motifs or endosomolytic co‑formulation), manufacturing scale‑up (mitigated by GMP‑scalable nanoparticle platforms), and unpredictable human biodistribution (mitigated by humanized BBB models and microphysiological‑system–based PK/PD testing).

Together, these paired mitigations form a practical roadmap that emphasizes staged PK/PD, safety, and target‑engagement testing prior to efficacy trials.

Key Takeaways:

• Aptamer platforms enable receptor‑mediated transcytosis—notably via transferrin and LDL receptor pathways—expanding noninvasive CNS delivery options.
• In vivo SELEX combined with computational optimization improves candidate fidelity and shortens discovery timelines for BBB‑penetrant aptamers.
• Targeted formulation (PEGylation, chemical backbone changes, nanoparticle conjugation) plus paired mitigations (stabilization, endosomal escape, GMP platforms, humanized models) creates a staged translational roadmap from PK/PD to clinical testing.