DNA‐mimic for Specific Surface Functionalization of Zr‐MOFs for Bacterial Targeting

ABSTRACT Nanosized metal–organic frameworks (MOFs) are versatile platforms used in biomedical applications due to their high loading capacity, large surface area, and tunable functionality. Without surface modifications, these nanoparticles lack cell specificity and are prone to aggregation and degradation in biological environments, reducing their effectiveness. Surface attachment of DNA via phosphate group coordination to zirconium‐based MOFs improves stability, but DNA binding remains non‐site‐specific due to the abundance of phosphate groups in its backbone, limiting DNA's addressability for further functionalization. To address this issue, we present a novel, significantly faster single‐step approach for the post‐synthesis modification of the external surface of PCN‐222 nanoparticles using an uncharged synthetic mimic of DNA, peptide nucleic acids (PNA). By using phosphate‐modified PNA, we achieve surface functionalization through coordination with the Zr 6 clusters on the MOF surface. The modification produced monodispersed nanoparticles and resulted in slowed drug‐release kinetics compared to unmodified nanoparticles. PNAs enhanced attachment efficiency and hybridization specificity compared to DNA coatings, allowing subsequent conjugation of protein targeting moieties and enabling bacterial targeting of drug‐loaded MOFs. This work introduces phosphotyrosine‐modified PNA as a superior, single‐step surface coating for PCN‐222, allowing controlled post‐functionalization with single‐stranded DNA (ssDNA) and expanding applications in biomedical and materials science.