Chirality is ubiquitous in nature and hard-wired into every biological system. Despite the prevalence of chirality in biological systems, controlling biomaterial chirality to influence interactions with cells has only recently been explored. Here, we present chiral-engineered supraparticles (SPs) that interact differentially with cells and proteins depending on their handedness. SPs coordinated with Dchirality demonstrated greater than three-fold enhanced cell membrane penetration in breast, cervical, and multiple myeloma cancer cells. We carried out quartz crystal microbalance with dissipation and isothermal titration calorimetry measurements to understand the mechanism of these chiral-specific interactions. Thermodynamically, D-SPs showed more stable adhesion to lipid layers composed of phospholipids and cholesterol compared to L-SPs. In vivo, D-SPs exhibited superior stability and longer biological half-lives likely due to opposite chirality and thus protection from endogenous proteins including proteases. This work showed that incorporating D-chirality into nanosystems enhanced uptake by cancer cells and prolonged in vivo stability in circulation, providing support for the importance of chirality in biomaterials. Thus, chiral nanosystems may have the potential to provide a new level of control for drug delivery systems, tumor detection markers, biosensors, and other biomaterial based devices.