Lectures and seminars Seminar: "Affinity is a molecule, selectivity is a crowd: phenotypic targeting and the repair of blood-brain barrier transport in Alzheimer's disease"
Welcome to a seminar with Professor Giuseppe Battaglia, Barcelona Institute of Science and Technology.
About the speaker
Giuseppe Battaglia is an ICREA Research Professor and Group Leader at the Institute for Bioengineering of Catalonia (IBEC) in Barcelona, where he founded and leads the Molecular Bionics group. His interdisciplinary research combines soft-matter physics, synthetic chemistry, engineering, and advanced microscopy to understand how molecules and nanoscale materials move across biological barriers and to translate these principles into new nanomedicines. A major focus of his work is the blood–brain barrier, including the mechanisms of receptor-mediated transport and their exploitation for targeted delivery of therapeutics to the brain.
About the talk
Pharmacology still designs around affinity. The key-lock model inherited from Ehrlich treats recognition as a single high-affinity event at a single receptor, ignoring two things any physiologist takes for granted: receptors are expressed in graded fashion across cell types, and binding happens in time, in a crowded and competitive environment. A high-affinity ligand engages its receptor wherever that receptor sits, so potency and promiscuity arrive together. I will present an alternative in which we engineer selectivity rather than discover it. Self-assembled copolymer micelles and vesicles offer three levers: a dense hydrophilic brush that suppresses non-specific adsorption, multivalent display of deliberately weak ligands whose combinatorial entropy gives a sharply non-linear dependence on receptor density [1,2], and multiplexing that barcodes the construct against the receptor and glycocalyx composition of the target cell [3]. At the blood-brain barrier, this does more than move cargo across. Multivalent engagement of LRP1 recruits the syndapin-2 tubular transcytosis pathway, with a clear avidity bias in which intermediate-avidity cargo is shuttled and high-avidity cargo is degraded [4]. The route is dysregulated in Alzheimer's disease [5]. In aged APP/PS1 mice, a single intravenous dose of LRP1-tuned polymersomes lowers parenchymal amyloid-beta by roughly 50% within one hour, restores the pathway within three days, and rescues hippocampal-dependent memory [6]. The logic is to restore a physiological clearance route rather than remove amyloid by brute force.
[1] Tian X, Angioletti-Uberti S, Battaglia G. On the design of precision nanomedicines. Science Advances 2020;6(4):eaat0919. doi 10.1126/sciadv.aat0919
[2] Liu M, Apriceno A, Sipin M, Scarpa E, Rodriguez-Arco L, Poma A, Marchello G, Battaglia G, Angioletti-Uberti S. Combinatorial entropy behaviour leads to range selective binding in ligand-receptor interactions. Nature Communications 2020;11:4836. doi 10.1038/s41467-020-18603-5
[3] Acosta-Gutiérrez S, Matias D, Avila-Olias M, Gouveia VM, Scarpa E, Forth J, Contini C, Duro-Castano A, Rizzello L, Battaglia G. A multiscale study of phosphorylcholine driven cellular phenotypic targeting. ACS Central Science 2022;8(7):891–904. doi 10.1021/acscentsci.2c00146
[4] Tian X, Leite DM, Scarpa E, Nyberg S, Fullstone G, Forth J, Matias D, Apriceno A, Poma A, Duro-Castano A, Vuyyuru M, Harker-Kirschneck L, Šarić A, Zhang Z, Xiang P, Fang B, Tian Y, Luo L, Rizzello L, Battaglia G. On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias. Science Advances 2020;6(48):eabc4397. doi 10.1126/sciadv.abc4397
[5] Leite DM, Seifi M, Ruiz-Perez L, Nguemo F, Plomann M, Swinny JD, Battaglia G. Syndapin-2 mediated transcytosis of amyloid-β across the blood–brain barrier. Brain Communications 2022;4(1):fcac039. doi 10.1093/braincomms/fcac039
[6] Chen J, Xiang P, Duro-Castano A, Cai H, Guo B, Liu X, Yu Y, Lui S, Luo K, Ke B, Ruiz-Pérez L, Gong Q, Tian X, Battaglia G. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport. Signal Transduction and Targeted Therapy 2025;10:331. doi 10.1038/s41392-025-02426-1
Host
Ana Teixeira, Department of Physiology and Pharmacology (ana.teixeira@ki.se)