Significance The ability of HIV-1 to rapidly develop resistance against various therapeutics remains a roadblock to finding a cure. Here we propose that nanoparticle-based therapeutics that mimic HIV-1 target cells by presenting clusters of CD4, the HIV-1 receptor, could prevent effective viral escape. We show that CD4 multimerization on the nanoparticle dramatically enhanced the neutralization potency and breadth compared with conventional CD4-based reagents that present only one or two copies of CD4. The CD4 nanoparticles neutralized a range of diverse HIV-1 strains, including patient isolates resistant to multiple broadly neutralizing antibodies. This work describes a new therapeutic direction that exploits the need of HIV-1 to bind CD4 on target cells, thus warranting further investigation for the potential development of a cure.