Self-assembled nanoparticles of rapamycin prodrugs for the treatment of multiple sclerosis.

Optimizing the design of nanoparticulate co-delivery systems of antigens and immunomodulators to induce antigen-specific immune tolerance effectively remains a challenge, constrained by low drug loading capacity and premature leakage of active ingredients. Here, we report a prodrug self-assembled nanoparticles (NPs) strategy to synergistically deliver antigen and rapamycin (RAPA) into antigen-presenting cells (APCs) by simply conjugating rapamycin with an aliphatic chain. These prodrug NPs can be efficiently taken up by APCs and then release rapamycin through cleavage of the linker by intracellular esterase. Compared to other nanocarriers, rapamycin prodrug NPs exhibit high drug loading capacity and high stability, providing more rational intracellular synchronous delivery of drugs. The prodrug NPs also demonstrate improved therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE) model mice compared with free antigen and rapamycin. Our findings provide new insights into the design of tolerogenic NPs for treating multiple sclerosis (MS). This delivery platform is also applicable for the alleviation of other autoimmune diseases.