Conformation-Stabilized Amorphous Nanocoating for Rational Design of Long-Term Thermostable Viral Vaccines

Despite the great potency of vaccines to combat infectious diseases, their global use is hindered by a lack of thermostability, which leads to a constant need for cold-chain storage. Here, aiming at long-term thermostability and eliminating cold-chain requirements of bioactive vaccines, we propose that efforts should focus on tailoring the conformational stability of vaccines. Accordingly, we design a nanocoating composed of histidine (His)-coordinated amorphous Zn and 2-methylimidazolate complex (His-aZn-mIM) on single nanoparticles of viral vaccines to introduce intramolecular coordinated linkage between viruses and the nanocoatings. The coordinated nanocoating enhances the rigidity of proteins and preserves the vaccine's activity. Importantly, integrating His into the original Zn-N coordinative environment symbiotically reinforces its tolerance to biological and hydrothermal solutions, resulting in the augmented thermostability following the Hofmeister effect. Thus, even after storage of His-aZn-mIM encapsulated Human adenovirus type 5 (Ad5@His-aZn-mIM) at 25 °C for 90 d, the potency loss of the coated Ad5 is less than 10%, while the native Ad5 becomes 100% ineffective within one month. Such a nanocoating gains thermostability by forming an ultrastable hydration shell, which prevents viral proteins from unfolding under the attack of hydration ions, providing a conformational stabilizer upon heat exposure. Our findings represent an easy-access biomimetic platform to address the long-term vaccine storage without the requirement of a cold chain.