A general strategy for site-oriented protein anchoring on metal–organic frameworks: HER2-targeted delivery using an engineered antibody fragment

Cancer therapies remain limited by poor selectivity and off-target toxicity, making biodistribution as critical as the drugs themselves. Antibodies have transformed cancer treatment by enabling the selective delivery of highly potent pharmaceutical ingredients (APIs) to diseased tissues, thereby increasing efficacy while reducing systemic side effects. This targeted approach has revived the clinical use of cytotoxic agents, which were previously considered too toxic without precise biodistribution. Building on this principle, antibody–drug conjugates (ADCs) combine these powerful drugs with antibodies to expand the therapeutic window and achieve controlled delivery to specific tumor sites. However, the low drug-to-antibody ratio and hydrophobic payloads often compromise ADC stability and limit the dosing. Nanoparticles offer an alternative route to achieve high-capacity drug delivery with controlled release, but few platforms combine efficient targeting with stable, site-specific conjugation. Metal–organic frameworks (MOFs) are distinguished by their high porosity, modular chemistry, and high drug-loading capacity. However, their translation has been hindered by the challenge of conjugating proteins to their external surfaces in a stable and oriented manner. Herein, we report the first fragment antibody (Fab)- conjugated MOF nanoparticles, using a phosphate anchoring group on the zirconium-based MOF PCN-128. This site-specific conjugation ensures optimal Fab orientation for selective binding to HER2 receptors and efficient cellular internalization of the drug. We confirmed stable conjugation, specific HER2 recognition, and enhanced cytotoxicity when loaded with the potent payload MMAF. Together, these results establish Fab-functionalized MOFs as a versatile, high-capacity drug delivery platform and open a new path for next-generation targeted cancer therapy.