CD44 is an endocytic hyaluronic acid (HA) receptor, and is overexpressed in many carcinomas. This has encouraged the use of HA to design CD44‐targeting carriers. This paper is about dissecting the mechanistic role of CD44. Here, HA‐decorated nanoparticles are used to deliver siRNA to both tumoral (AsPC‐1, PANC‐1, HT‐29, HCT‐116) and non‐tumoral (fibroblasts, differently polarized THP‐1 macrophages, HUVEC) human cell lines, evaluating the initial binding of the nanoparticles, their internalization rate, and the silencing efficiency (cyclophilin B (PPIB) gene). Tumoral cells internalize faster and experience higher silencing than non‐tumoral cells. This is promising as it suggests that, in a tumor, HA nanocarriers may have limited off‐target effects. More far‐reaching is the inter‐relation between the four parameters of the study: CD44 expression, HA binding on cell surfaces, internalization rate, and silencing efficiency. No correlation is found between binding (an early event) and any of the other parameters, whereas silencing correlates both with speed of the internalization process and CD44 expression. This study confirms on one hand that HA‐based carriers can perform a targeted action, but on the other it suggests that this may not be due to a selective binding event, but rather to a later recognition leading to selective internalization.