GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327133/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327133GEOGSEfalseVirus-like particles enable targeted gene engineering and pooled CRISPR screening in primary human myeloid cells [CRISPRoff]Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing, and epigenetic silencing. Furthermore, in combination with AAV-mediated donor delivery, this approach enables site-specific integration of large DNA sequences via homology-directed repair. We also developed SLICeVLP, a system combining sgRNA delivery via VPX-lentivirus with Cas9 protein delivery via engineered virus-like particles (eVLPs), and applied it to perform pooled loss-of-function screens and Perturb-seq in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity in engineered HER2 CAR-macrophages. Taken together, this platform enables unbiased functional genomics in primary human myeloid cells, with direct implications for myeloid cell therapy design.2026/04/08GSE327133GSM9649095GSM9649073GSM9649094GSM9649072GSM9649075GSM9649074GSM9649077GSM9649076GSM9649079GSM9649078GSM9649091GSM9649090GSM9649071GSM9649093GSM9649092GSM9649070GSM9649084GSM9649083GSM9649086GSM9649085GSM9649088GSM9649087GSM9649068GSM9649089GSM9649080GSM9649082GSM9649081GSM964906934284327133Homo sapiens