Polyethylenimine–Poly(lactic-co-glycolic acid)(2) Nanoparticles Show an Innate Targeting Ability to the Submandibular Salivary Gland via the Muscarinic 3 Receptor

[Image: see text] Polymeric nanoparticles have been extensively explored for biomedical applications, especially as framework materials for the construction of functional nanostructures. However, less attention has been paid to the inherent biological activities of those polymers. In this work, one of the commonly used polymers in gene and protein delivery, polyethylenimine–poly(lactic-co-glycolic acid)(2) (PEI–PLGA), was discovered by accident to be able to mediate the nanoparticles to target the submandibular salivary glands of mice after intravenous injection. PEI–PLGA nanoparticles with an unmodified PEI surface selectively accumulated in submandibular salivary glands with ex vivo and in vitro study, suggesting that a ligand–receptor interaction between PEI and muscarinic acetylcholine receptor subtype 3 (M3 receptor) contributed to this affinity. Docking computation for the molecular binding mode between PEI segments and M3 receptor indicated the way they interacted was similar to that of the FDA-approved specific M3 receptor antagonist, tiotropium. The key amino acids mediated this specific interaction between PEI–PLGA nanoparticles and M3 receptor were identified via a simulated alanine mutation study. This work demonstrates the unique characteristic of PEI–PLGA nanoparticles, which may be useful for the development of muscarinic receptor targeted nanomedicines and should be taken into consideration when PEI-based nanoparticles are applied in gene delivery.