Background: Human immunodeficiency virus (HIV)-infected active and latent C-C motif chemokine receptor-5 (CCR5) expressing long-lived T-cells are the primary barrier to HIV/AIDS eradication. Broadly neutralizing antibodies and latency-reversing agents are the two most promising strategies emerging to achieve ‘functional cure’ against HIV infection. Antiretrovirals (ARVs) have shown to suppress plasma viral loads to non- detectable levels and other strategies have demonstrated a ‘functional cure’ against HIV infection is achievable. Strategies are effective at inducing direct or immune-mediated cell death of latent HIV+ T-cells but have shown respective limitations. We designed a novel targeted ARVs-loaded nanoformulation that combines a CCR5 monoclonal antibody and antiretroviral drugs (ARV) as a dual protection strategy to promote HIV ‘functional cure’. The modified CCR5 monoclonal antibody (xfR5 mAb) surface-coated dolutegravir (DTG) and tenofovir alafenamide (TAF) loaded nanoformulation (xfR5-D+T NPs)Results: The nanoformulation was uniformly sized <250 nm, with 6.5 times enhanced antigen-binding affinity compared to naïve xfR5 mAb, and provided prolonged DTG and TAF intracellular retention. The multivalent and sustained drug release properties of xfR5-D+T NPs enhance the protective efficiency against HIV by approximately 12, 3, and 5 times compared to naïve xfR5 mAb, D+T NP alone, and xfR5 NPs, respectively. Further, the nanoformulation demonstrated high binding-affinity to CCR5 expressing CD4+ cells, monocytes, and other HIV prone/latent T-cells by 25, 2, and 2 times, respectively. Finally, during short-term pre-exposure prophylaxis, the xfR5-D+T NPs induced a protective immunophenotype, with boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. Treatment with xfR5-D+T NPs to HIV-infected T-cells induced a defensive/activated immunophenotype with boosted naïve, Th, central memory, TM, EM, E, and activated cytotoxic T-cells population.Conclusion: This dual-action targeted nanoformulation could potentially become a multifactorial solution to achieve a “functional cure.”