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A 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.

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