Dendrimers are nanosized, nonlinear, hyperbranched polymers whose overall 3D shape is key for their biological activity. Poly­(PhosphorHydrazone) (PPH) dendrimers capped with aza-bisphosphonate (ABP) end groups are known to have anti-inflammatory properties enabling the control of inflammatory diseases in different mouse models. Here we screen the anti-inflammatory activity of a series of PPH dendrimers bearing between 2 and 16 ABP end groups in a mouse model of arthritis and confront the biological results with atomistic simulations of the dendrimers. We show that only the PPH dendrimers capped with 10 and 12 ABP end groups can control the flare of the inflammatory disease. All-atom accelerated molecular dynamics simulations show that dendrimers with a low number of ABP end groups are directional but highly flexible/dynamic and have thereby limited efficiency in establishing multivalent interactions. The largest dendrimer appears as nondirectional, having 16 ABP end groups forming patches all over the dendrimer surface. Conversely, intermediate dendrimers having 10 or 12 ABP end groups reach the best compromise between the number of surface groups and their stable directional gathering, a real maximization of multivalency.