Injectable Liposome Based Supramolecular Hydrogels for the Programmable Release of Multiple Protein Drugs

Directing and manipulating biological functions is at the heart of next-generation biomedical initiatives such as tissue and immuno-engineering. Yet, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Using lipid nanotechnology and the principles of supramolecular self-assembly, we have developed an injectable liposomal nanocomposite hydrogel platform to precisely control drug presentation through programing of the co-release of multiple protein drugs. These liposomal hydrogels exhibited robust shear-thinning and self-healing behaviors enabling facile injectability for local drug delivery applications. By integrating modular lipid nanotechnology into this hydrogel platform, we introduced multiple mechanisms of protein release based on liposome surface chemistry. When injected into immuno-competent mice, these liposomal hydrogels exhibited formulation-dependent rates of dissolution and excellent biocompatibility. To fully validate the utility of this system for multi-protein delivery, we demonstrated the synchronized, sustained, and localized release of IgG antibody and IL-12 cytokine in vivo, despite the significant size differences between these two proteins. Overall, these liposomal nanocomposite hydrogels are a highly modular platform technology with the ability the mediate orthogonal modes of protein release and the potential to precisely coordinate biological cues both in vitro and in vivo. ### Competing Interest Statement S.C., A.K.G., J.H.K., and E.A.A. are on a pending patent reporting the liposomal hydrogel technology described in this article (U.S. Patent Application No. 63/177373.