Multifunctional Click Hyaluronic Acid Nanogels for Targeted Protein Delivery and Effective Cancer Treatment in Vivo

Protein therapeutics offer a most effective treatment for many human diseases, including diabetes, cardiovascular diseases, and malignant tumors. Unlike most chemotherapeutics that often cause notorious side effects, many protein drugs possess a high specificity and reduced systemic toxicity. Notably, clinically used protein drugs are mostly limited to those that have extracellular effects. Protein drugs that have intracellular targets do represent a large family of protein biologics that have not been introduced into the clinic, because of the absence of translatable intracellular protein delivery vehicles. Here we report efficient and targeted cancer protein therapy in vivo by bioresponsive fluorescent photoclick hyaluronic acid (HA) nanogels. Two intracellular protein drugs, cytochrome c (CC) and granzyme B (GrB), are loaded into the nanogels with preserved bioactivity. CC- and GrB-loaded HA nanogels can effectively target and release proteins to CD44 positive MCF-7 and A549 cancer cells, yielding striking antitumor effects with a half-maximal inhibitory concentration thousands of times lower than those of clinical chemotherapeutics. Remarkably, GrB-loaded HA nanogels at a low dose of 3.8–5.7 nmol of GrB equivalents/kg exhibit complete suppression of tumor growth and minimal adverse effects in nude mice bearing subcutaneous MCF-7 human breast tumor and orthotopic A549 human lung tumor xenografts.