Broadly neutralizing antibodies (bNAbs) directed to HIV-1 have shown promise at suppressing viremia in animal models. However, the use of bNAbs for the central nervous system (CNS) infection is confounded by poor penetration of the blood brain barrier (BBB). Typically, antibody concentrations in the CNS are extremely low; with levels in cerebrospinal fluid (CSF) only 0.1% of blood concentrations. Using a novel nanotechnology platform, which we term nanocapsules, we show effective transportation of the human bNAb PGT121 across the BBB in infant rhesus macaques upon systemic administration up to 1.6% of plasma concentration. We demonstrate that a single dose of PGT121 encased in nanocapsules when delivered at 48h post-infection delays early acute infection with SHIVSF162P3 in infants, with one of four animals demonstrating viral clearance. Importantly, the nanocapsule delivery of PGT121 improves suppression of SHIV infection in the CNS relative to controls. Author summary: In patients where HIV-1 is fully suppressed by antiretroviral drugs, HIV-1 still persists in reservoirs. If antiretroviral drugs are stopped, the virus will emerge from these reservoirs and re-seeds systemically. The central nervous system (CNS) is proposed to be a tissue compartment that harbors other HIV-1 reservoirs. A key obstacle that constrains the treatment for the CNS infection is the blood–brain barrier (BBB), a highly restrictive barrier separating the circulating blood from the brain and extracellular fluid in the CNS, which impedes ~98% of the small molecule therapeutics and almost all macromolecules including broadly neutralizing antibodies (bNAbs) directed to HIV-1. Our "nanocapsule" strategy is based on a nanotechnology wherein bNAb molecules are encapsulated within nanocapsules of which the surface contains abundant choline and acetylcholine analogues. This design allows the nanocapsules to effectively cross the BBB to deliver bNAbs into the CNS upon systemic administration and show an impact of bNAb on CNS reservoirs in SHIV infected infant macaques. [ABSTRACT FROM AUTHOR]