Polyphenolic flavonoids have shown promising therapeutic effects in spinal cord injury (SCI) due to their outstanding antioxidative and anti-inflammatory functions. However, some of their inherent physicochemical properties such as poor water solubility, low stability and bioavailability, and strong biological metabolism, severely limit the clinical applications. Moreover, the current polyphenolic flavonoid delivery systems have some problems such as sophisticated preparation processes, low yields, high cost, and lack of targeted traceless release. To address those critical issues, we have proposed a general, facile and robust delivery strategy to prepare functional nanoparticles (NPs) through one-pot assembly of polyphenolic flavonoids and their molecular adaptors. Polyethylene glycol (PEG), one of the most widely used biocompatible polymers, and o-aldehyde phenylboric acid, a kind of small molecule adapters, were selected to form NPs with flavonoids. In addition to excellent anti-inflammatory and antioxidant properties, resulting NPs have also demonstrated possess the targeted enrichment of high reactive oxygen species levels in damaged areas and long-term blood circulation stability, which worked well for SCI therapy. This strategy takes the most commonly used PEG as an example, which can be further applied to many other types of hydrophilic polymers with amino groups, such as polysaccharides, peptides and proteins etc.