Coordination of rigidity modulation and targeting ligand modification on orally-delivered nanoparticles for the treatment of liver fibrosis

Although the individual role of ligand modification or rigidity modulation on oral administration of nanoparticle (NP) has been investigated, how they mutually affect each other remains to be elucidated. Here, we fabricated different rigidity NP with or without surface decoration of FcBP, a neonatal Fc receptor domain-binding peptide. In vitro studies showed that, without FcBP modification, stiff NP had higher transcytosis efficiency across the epithelium than softer NP, due to the different endocytosis mechanisms, intracellular trafficking routes, and exocytosis rate. Notably, after FcBP modification, such difference was narrowed, in a manner that was more favorable for softer NP to “catch up” with stiff NP, suggesting ligand modification was more conducive to exert transcytosis-promoting efficacy on softer NP. In vivo experiments demonstrated that, for ligand-free NP, high rigidity was required for efficient oral absorption and liver distribution. Further FcBP modification decreased that “rigidity threshold”, and expanded the feasible rigidity range from stiff NP to softer NP. Upon oral administration, FcBP-modified dexamethasone-loaded softer NP achieved a therapeutic efficacy comparable with stiff NP on alleviating liver fibrosis. Collectively, our study highlighted the necessity of coordinating ligand modification and rigidity modulation for oral drug delivery. We fabricated different rigidity NP with or without surface decoration of FcBP, a neonatal Fc receptor domain-binding peptide. Our results revealed that ligand-free NP, high rigidity was required for efficient oral absorption. Further FcBP modification decreased that “rigidity threshold”, and expanded the feasible rigidity range from stiff NP to softer NP. [Display omitted] •Ligand endowed nanocarriers with the ability of active-targeting.•The rigidity of ligand-modified NP would regulate receptor-mediated transcytosis.•Ligand broadened the range of feasible rigidity.