biostudies-literatureDu MNational Natural Science Foundation of China (National Science Foundation of China)514https://www.ebi.ac.uk/biostudies/studies/S-EPMC12804944biostudies-literatureUnknown17(1)While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous adminisNature communicationsChimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.PMC128049448226113855382373898Liu HLiu JWang CZhang HZhao ZMa WWei PWang SGong NWang WWang XZhou FWang YYang HDuan BBai YLi LXue XLi NLi XChen AHuang YLi TZhang ZGuan XZhang XLei YHan GZhu XDu MJian YGao SDuan YfalseChimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous adminis2025-01-01T00:00:00Z2025 Dec2026-06-06T16:05:39.213Z2026-06-02T03:12:13.219ZS-EPMC128049444137219610.1038/s41467-025-67207-4