Today’s scientific society lies at the verge of discovering a successful gene therapy against HIV. Still, two major barriers preclude a successful outcome: (i) heterogeneity of the HIV reservoir impedes the use of generic gene targeting strategies and (ii) vector delivery to latent HIV reservoirs is inefficient. TENACITY seeks to overcome these restrictions by combining a patient-individualized CRISPR-based strategy with two completely novel delivery systems. Single guide (sg)RNAs targeting the long terminal repeats (LTRs) of patient-specific HIV proviral quasispecies will be combined with the bacterial endonuclease Cas9 or Cas9 mRNA into nanomaterials engineered to specifically target HIV-susceptible cells (CD4+ cells). Two delivery systems will be compared: (i) lipid nanoparticles conjugated to anti-human CD4 nanobodies (HIV-Nanoblade Stars) and (ii) murine leukemia virus-like particles expressing HIV envelope protein (HIV-Nanoblades). TENACITY’s nanomaterials will be validated in a newly designed patient-adapted in vitro T cell model and in a patient-adapted humanized mouse model. In both models, the use of cells transduced with patient-derived LTR loci will allow validation of our personalized gene targeting strategy. The approach we propose will enable efficient and specific removal of full-length HIV genomes from infected patients. Together, TENACITY has a high potential to lay the foundation to make a final cure for HIV.