Metal-organic framework nanoparticles hitchhiking on T cells for protein delivery to boost anticancer immunotherapy

Immunosuppressive tumor microenvironment (TME) limits the response to immunotherapy based on programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade. Here, pH-sensitive metal-organic framework nanoparticles (MOF NPs) which efficiently co-encapsulate hemoglobin (Hb) and catalase (CAT) and preserve their activities in physiological conditions are fabricated, embedded in liposome to improve water dispersity, and conjugated with PD-1 antibody (aPD-1) for binding PD-1+ T cells. The nanodrug (C&H@MOF/PL-A) thus prepared hitchhikes on circulating PD-1+ T cells for efficient protein delivery to tumor sites. The tumor weak acidity may detach the functionalized MOF from T cells while still leaving aPD-1 to bind T cells for immune checkpoint blockade (ICB). Finally, the MOF NPs release CAT and Hb which catalyzes oxygen production and stores oxygen in situ, respectively, for a long-term hypoxia relief. Consequently, the immunosuppression in TME is reversed to boost an ICB-based immunotherapy against colorectal carcinoma.