Photodynamic therapy (PDT)‐mediated cancer immunotherapy is attenuated due to the dysfunction of T cells in immunosuppressive tumor microenvironment (TME). Cholesterol metabolism plays a vital role in T cell signaling and effector. While the metabolic fitness of tumor infiltrating CD8+ T cells is impaired by nutrition restriction in TME and accumulated metabolites by tumor cells. Here a matrix metalloproteinase‐2‐sensitive tumor‐penetrable nanovesicle is designed to regulate cholesterol metabolism pathway for enhancing photodynamic cancer immunotherapy. The nanovesicles accumulate in tumor and release internalizing RGD to promote deep penetration. Released avasimibe from the nanovesicles simultaneously blocks cholesterol metabolism in CD8+ T and tumor cells, thus reinvigorating the functions of T cells and suppressing the migration of tumor cells. Immune responses induced by PDT‐triggered immunogenic cell death are further improved with cholesterol metabolism blockage. Compared with PDT alone, the designed nanovesicles display enhanced tumor growth inhibition in B16‐F10 mouse tumor model. The approach provides an alternative strategy to improve photodynamic cancer immunotherapy by cholesterol metabolism intervention.
Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery. On the one hand, bioorthogonal reactions improve therapeutic agent delivery to target sites, overcoming off-target distribution. On the other hand, nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions, providing approaches to developing multi-functional drug delivery systems (DDSs). In this review, we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups. We then highlight recent breakthroughs in developing active targeting DDSs to tumors, immune systems, or bacteria by bioorthogonal chemistry, as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs (biomimetic DDSs, cell-based DDSs, bacteria-based and phage-based DDSs) and hydrogels. Finally, we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery. We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.
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