Reversible Shielding and Immobilization of Liposomes and Viral Vectors by Tailored Antibody‐Ligand Interactions

Controlling the time and dose of nanoparticulate drug delivery by administration of small molecule drugs holds promise for efficient and safer therapies. This study describes a versatile approach of exploiting antibody‐ligand interactions for the design of small molecule‐responsive nanocarrier and nanocomposite systems. For this purpose, antibody fragments (scFvs) specific for two distinct small molecule ligands are designed. Subsequently, the surface of nanoparticles (liposomes or adeno‐associated viral vectors, AAVs) is modified with these ligands, serving as anchor points for scFv binding. By modifying the scFvs with polymer tails, they can act as a non‐covalently bound shielding layer, which is recruited to the anchor points on the nanoparticle surface and prevents interactions with cultured mammalian cells. Administration of an excess of the respective ligand triggers competitive displacement of the shielding layer from the nanoparticle surface and restores nanoparticle‐cell interactions. The same principle is applied for developing hydrogel depots that can release integrated AAVs or liposomes in response to small molecule ligands. The liberated nanoparticles subsequently deliver their cargoes to cells. In summary, the utilization of different antibody‐ligand interactions, different nanoparticles, and different release systems validates the versatility of the design concept described herein. This study illustrates the development of nanocarrier and nanocomposite systems responsive to the presence of specific small molecules. Functionalized antibody fragments bind to nanoparticles surface‐modified with specific small molecules, preventing association with cells either by providing a polymer shielding layer, or by allowing formation of a hydrogel depot. Addition of the cognate small molecule competitively displaces the interaction, restoring cell binding.