Small interfering RNA (siRNA) is an emerging therapeutic modality for a varietyof diseases, including cancer, as siRNA can silence target genes in asequence-specific manner. The effective delivery of siRNA remains a majorchallenge due to rapid clearance by macrophages in the systemic environment.Nonspecific interactions with the serum proteins in the bloodstream contributeto macrophage uptake, limiting circulation time, thereby reducing the effectivedelivery of siRNA to the target site. Here, we report the efficient delivery ofsiRNA to cancer cells using hyaluronic acid (HA)-coated cationic polymericnanovector (PONI-Guan)/siRNA polyplexes. The guanidinium-functionalized polymersself-assemble with siRNA and enable cytosolic delivery. HA serves as anoninteracting protective shield on the polyplexes that prevent macrophageuptake in vitro. These nanovectors facilitate efficient siRNAdelivery to 4T1 triple-negative breast cancer cells in vitro,with a 4:1 selectivity relative to macrophages. Further, HA-coated polyplexesdemonstrated efficient STAT3 gene knockdown (~50%) in 4T1 cells. Intravenousadministration of HA-coated polyplexes in 4T1 tumor-bearing mice showedsignificantly (~50%) decreased accumulation in clearance organs, in comparisonto the PONI-Guan polyplexes. Collectively, HA-coated polyplexes provide aneffective strategy for selective siRNA delivery to tumor cells while avoidingmacrophage uptake.