Despite the tremendous success of combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection, the durability and persistence of latent reservoirs of HIV-infected cells in HIV-infected patients remain obstacles to achieving HIV cure. While technically challenging, the most direct means to eradicate latent reservoirs is to destroy the HIV provirus, thus ensuring that HIV virions are not produced while preserving resident cells. Transcription activator-like effector nucleases (TALEN)─a genome editing method with high DNA targeting efficiency─have been investigated as a potential gene therapy by disrupting the HIV-1 coreceptor CCR5 genes in HIV target cells or HIV proviral DNA in infected cells. However, the transduction and editing efficiencies are low in primary cells and vary by cell type. Using a nanotechnology platform, which we term nanocapsules, the TALEN protein can be effectively delivered into primary cells and escape from endosome/lysosome sequestration. We report that TALEN nanocapsules can effectively mutagenize the HIV-1 proviral DNA integrated into two primary HIV-1 reservoir cells─T cells and macrophages, such that replication and/or reactivation from latency is aborted. We envision that this study provides a useful platform to deliver a wide range of DNA-modifying enzymes for effective HIV therapy.