A Nanobody–Bioorthogonal Catalyst Conjugate Triggers Spatially Confined Prodrug Activation for Combinational Chemo-immunotherapy

Checkpoint
inhibitors have been used with chemotherapy to improve
antitumor efficacy. However, overcoming the immunosuppressive effect
of chemotherapeutics remains a challenge. We report a nanobody–catalyst
conjugate Ru-PD-L1 by fusing a ruthenium catalyst to an anti-PD-L1
nanobody. After administration of Ru-PD-L1 and a doxorubicin (DOX)
prodrug, Ru-PD-L1 disrupts the PD-L1/PD-1 interaction and catalyzes
the uncaging of the DOX prodrug. The spatially confined release of
DOX reduces its systemic toxicity and leads to immunogenic cell death
(ICD). The induced ICD triggers antitumor immune responses, which
are further amplified by PD-L1 blockade to elicit synergistic chemo-immunotherapy,
substantially increasing the number of tumor-infiltrating T-cells
by 49.7% compared with the controls, thereby exhibiting high antitumor
activity and low cytotoxicity in murine models. The combinational
treatment could inhibit the growth of mice tumors by 67.7% compared
to the control group. This combinational approach circumvents the
negative immunogenic effects of chemotherapeutics and provides a potential
chemo-immunotherapy strategy for human cancer treatment.