Once a nanoparticle is exposed to a biologic environment (e.g., after intravenous injection), it immediately interacts with thousands of biomolecules, from plasma proteins to red blood cells. These nanoparticle-biomolecule interactions dictate many aspects of nanoparticle performance in vivo, such as biodistribution, uptake by clearance organs, and recognition by the immune system. However, we lack a detailed understanding of how nanoparticle formulation impacts biomolecule interactions, which limits our ability to rationally design nanoparticles. This work investigates how nanoparticle formulation influence interactions of the nanoparticle with biologic molecules, with two focus areas: 1) How biologic molecules influence release and delivery of small molecule drugs from liposomes 2) How the conjugation chemistry on nanoparticle surfaces affects recognition of nanoparticles by the immune system. As model particles, we utilized liposomes loaded with various small molecule drugs and surface-conjugated with antibodies. Regarding focus area #1, small molecule loading, release, and pharmacokinetics were assessed with mass spectrometry and various bio-relevant in vitro and in vivo release assays. We show that red blood cells are the biologic entity with the most significant influence on drug release, but only for hydrophobic drugs loaded into the lipid membrane, and not for drugs loaded into the aqueous liposome core. Regarding focus area #2, we show that the most popular conjugation chemistries directly participate in activation of the complement cascade of plasma proteins. We found that the mechanism of complement activation varies dramatically between the conjugation chemistries. Dibenzocyclooctyne caused aggregation of conjugated antibodies, while thiol-maleimide chemistry activated complement because free maleimide bonded to albumin in plasma, and clustered albumin was then attacked by complement. Using these mechanistic insights, we engineered solutions that reduced the activation of complement for each of these classes of conjugation chemistry. These results point out that nanoparticle formulations must be designed with an eye toward interactions with biologic entities such as red blood cells and complement proteins.