Structural variants (SVs) are a major source of genomic diversity, yet their discovery remains challenging due to repetitive genomic contexts, alignment ambiguity and the trade-off between sequencing cost and read length. Here we introduce HitSV, which implements repetitiveness- and signature-density-aware breakpoint recognition coupled with precise haplotype-resolved local assembly, thereby enabling base-resolution SV reconstruction and genotyping in various sequencing technologies. On the HG002 benchmark, HitSV achieved 15-72% (long read), 10-36% (short read) and 12% (hybrid sequencing), respectively, higher genotype F1 scores than state-of-the-art SV callers. Applied to the 1KGP phase 4 cohort, HitSV expanded the SV callset by 31.5%, substantially reshaping allele-frequency landscapes. In a large Chinese long-read cohort, HitSV uncovered tandem-repeat-mobile-element composite arrays as a prevalent, multi-allelic class of complex SVs, highlighting composite repeat architectures as an important and previously underrecognized contributor to human structural variation.

Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo. CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1[b]-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.