Computational design of non-porous pH-responsive antibody nanoparticles.
Erin C YangRobby DivineMarcos C MirandaAndrew J BorstWill ShefflerJason Z ZhangJustin DecarreauAmijai SaragoviMohamad AbediNicolas GoldbachMargaret AhlrichsCraig DobbinsAlexis HandSuna ChengMila LambPaul M LevineSidney ChanRebecca SkotheimJorge FallasGeorge UedaJoshua M LubnerMasaharu SomiyaAlena KhmelinskaiaNeil P KingJulien S BakerPublished in: Nature structural & molecular biology (2024)
Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery.