Therapeutic antibodies (e.g., trastuzumab, TRA) against human epidermal growth factor receptor 2 (HER2)-positive breast cancers have shown benefits in controlling primary tumors, yet are ineffective against brain metastases due to their inability to cross the blood-brain barrier (BBB). A novel hybrid nanoconstruct system is designed to deliver trastuzumab to brain metastasis of HER2-positive breast cancer via a two-step sequential targeting approach. Self-assembly of a polysorbate 80 (PS 80)-containing polymer, lipid, and polymer-conjugated TRA forms hybrid nanoconstructs (TRA-terpolymer nanoparticles (TPN)) with high encapsulation efficiency and bioactivity. The PS 80 moiety enables the first-step targeting and receptor-mediated trancytosis across BBB is demonstrated in vitro with a 3D human BBB model in healthy and brain tumor-bearing mice. The subsequent partial dissociation of the nanoconstructs exposes the encapsulated TRA for the second-step targeting to HER2-positive cancer cells in the brain. Intravenously injected TRA-TPN delivers 50-fold TRA compared to free TRA to the brain metastasis of HER2-positive breast cancer. Treatment with TRA-TPN increases tumor cell apoptosis by 4-fold, inhibits tumor growth by 43-fold, and prolongs median survival by >1.3-fold compared to free TRA, without causing noticeable organ toxicity. These findings suggest the two-step targeted nanoconstruct system is promising for shuttling therapeutic antibodies to treat central nervous system diseases.