Biosynthetic and Unfolded Protein Nanocarriers for Chemotherapeutic Drugs in Oral Cancers: Improved Bioavailability and Safety of Chemotherapeutics

Abstract Conventional nanocarriers for oral squamous cell carcinoma (OSCC) chemotherapy are greatly limited due to undesired adverse effects and low bioavailability. As an FDA‐approved protein nanocarrier, i.e., human serum albumin (HSA), the folded conformation limits its versatility for loading OSCC chemotherapeutics with different molecular structures. Here, a new type of biosynthetic and unfolded protein nanocarrier is developed, which shows outstanding efficiency for loading and delivering a series of chemotherapeutic agents, including chlormethine, docetaxel, and pingyangmycin. Moreover, all the nanoformulated drugs exhibit rather prolonged half‐lives as evidenced by sustained release of the payloads for up to 5 days. In stark contrast to polymeric micelles and liposomes, in this system the loading efficiency is increased 3–4 times and the corresponding half‐life is even extended one order of magnitude. Enhanced antitumor effects in rat OSCC models are realized. Additionally, off‐target side effects such as liver and kidney toxicity and immunogenicity are significantly mitigated with the nanomedications. Thus, this versatile formulation strategy boosts the efficacy, bioavailability, and safety of chemotherapeutics in OSCC therapy, and promisingly enables combined chemotherapy in comprehensive treatment for OSCC.