GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327354/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327354GEOGSEfalseVirus-like particles enable targeted gene engineering and pooled CRISPR screening in primary human myeloid cells [RNA-seq Exp3]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.2026/04/08GSE327354GSM9654255GSM9654244GSM9654254GSM9654243GSM9654257GSM9654246GSM9654256GSM9654245GSM9654251GSM9654250GSM9654253GSM9654242GSM9654241GSM9654252GSM9654248GSM9654258GSM9654247GSM965424934284327354Homo sapiens