AbstractA new class of polymer spherical nucleic acid (SNA) conjugates comprised of poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle (NP) cores is reported. The nucleic acid shell that defines the PLGA‐SNA exhibits a half‐life of more than 2 h in fetal bovine serum. Importantly, the PLGA‐SNAs can be utilized to encapsulate a hydrophobic model drug, coumarin 6, which can then be released in a polymer composition‐dependent tunable manner, while the dissociation rate of the nucleic acid shell remains relatively constant, regardless of core composition. Like prototypical gold NP conjugate SNAs, PLGA‐SNAs freely enter Raw‐Blue cells and can be used to activate toll‐like receptor 9 in a sequence‐ and dose‐dependent manner. Taken together, the data show that this novel nanoconstruct provides a means for controlling the release kinetics of encapsulated cargos in the context of the SNA platform, which may be useful for developing combination therapeutics.