Orthogonal Chemistry Enables Precision Nanoparticle Cofunctionalization for Tuning Immune Stimulation and Antigen Presentation.

Combination therapies are increasingly utilized to treat complex diseases, capitalizing on drug synergies to potentiate overall therapeutic responses and improve patient outcomes. Drug delivery systems improve combination therapy access to tissues and cells of interest, but attempting to coconjugate multiple drugs to the same carrier can limit the precision of drug ratios or release behaviors, making it challenging to optimize the delivery of the individual drug compounds. Here, thiol-disulfide exchange and strain-promoted click chemistry are leveraged in combination with an established polymeric nanoparticle platform to achieve chemistry-defined control over both the conjugation ratio and release behavior of coconjugated moieties. When applied as a subunit vaccine platform, this system enables the modulation of lymph node dendritic cell maturation and antigen presentation. The results presented here thus demonstrate a versatile dual-functional drug delivery platform to overcome existing challenges in combination therapy delivery.