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.

No abstract

The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received significant attention as a cancer therapeutic due to its ability to selectively trigger cancer cell apoptosis without causing toxicity in vivo. While TRAIL has demonstrated significant promise in preclinical studies in mice as a cancer therapeutic, challenges including poor circulation half-life, inefficient delivery to target sites, and TRAIL resistance have hindered clinical translation. Recent advances in drug delivery, materials science, and nanotechnology are now being exploited to develop next-generation nanoparticle platforms to overcome barriers to TRAIL therapeutic delivery. Here, we review the design and implementation of nanoparticles to enhance TRAIL-based cancer therapy. The platforms we discuss are diverse in their approaches to the delivery problem and provide valuable insight into guiding the design of future nanoparticle-based TRAIL cancer therapeutics to potentially enable future translation into the clinic.