Targeted Covalent Nanodrugs Reinvigorate Antitumor Immunity and Kill Tumors via Improving Intratumoral Accumulation and Retention of Doxorubicin

Specifically improving the intratumoral accumulation and retention and achieving the maximum therapeutic efficacy of small-molecule chemotherapeutics remains a considerable challenge. To address the issue, we here reported near-infrared (NIR) irradiation-activatable targeted covalent nanodrugs by installing diazirine-labeled transferrin receptor 1 (TfR1)-targeted aptamers on PEGylated phospholipid-coated upconversion nanoparticles followed by doxorubicin loading. Targeted covalent nanodrugs recognized and then were activated to covalently cross-link with TfR1 on cancer cells by 980 nm NIR irradiation. Systematic studies revealed that they achieved >6- and >5.5-fold higher intratumoral accumulations of doxorubicin than aptamer-based targeted nanodrugs at 6 and 120 h post intravenous injection, respectively. Based on high drug delivery efficacy, targeted covalent nanodrugs boosted doxorubicin-induced immunogenic cell death, activated antitumor immune responses and shrank the sizes of both primary and distant tumors, and displayed better therapeutic efficacy and less adverse effect than targeted nanodrugs and commercial Doxil in 4T1 syngeneic breast tumor model featuring an immunosuppressive microenvironment. By integrating the specificity of molecular recognition, the reactivity profile of diazirine and the accuracy of light manipulation with nanodrug supremacy, our targeted covalent nanodrugs could be expected as a longer-term and efficient strategy to improve anticancer therapeutic efficacy of chemotherapeutics.