Facile Label-Free Cytomembrane Reverse Coating Strategy via Membrane Carbohydrate–Lectin Self-Assembly for the Targeted Discovery of Natural Drug Candidates

The ordered cytomembrane coating nanotechnologies have aroused increasing attention in various medical aspects, including drug screening. However, this ordered coating necessitates prior chemical or biological labeling of the cytomembrane, which threatens the preservation of the membrane protein bioactivity on nanoparticles and introduces nonspecific adsorption. This paper reports the facile development of a label-free osteoblast membrane reversely coated with magnetic hydrochar nanospheres (OMR@MHNs) via the self-assembly of concanavalin A (ConA)-bonded MHNs and OMs. The sucrose-derived MHNs were covalently functionalized with ConA via aqueous amidation with its residual amino groups. Without any additional modification on OMs, the ordered reverse OM coverage onto MHNs with full exposure of the inner surface was driven by the specific affinity interaction between the immobilized concanavalin and inherent extracellular saccharides of the osteoblast. This interaction also achieved improved OM capacity and biocomposite stability. Using bioactive OMR@MHNs as the extraction nanoplatform, four specific ingredients including two new potentially osteogenetic chemicals of diphylloside A and sagittatoside C targeting the inner surface of OMs were smoothly identified from <i>Epimedium brevicornu</i> Maxim, which were hardly discovered via normal OM disorderly bonded MHNs. As verified by cell, molecular docking, cellular thermal shift assay, Western blot, and zebrafish tests, diphylloside A and sagittatoside C showed significant antiosteoporotic actions with binding membrane proteins of EPH receptor B4 and fibroblast growth factor receptor 1. This research facilitated the facile label-free construction of ordered bioadsorbent and high-activity screening of natural drugs.