Molecularly Imprinted Polymers for Highly Specific Bioorthogonal Catalysis inside Cells.

Transition metal catalysts (TMCs) mediated bioorthogonal catalysis expand the chemical possibilities within cells. Developing synthetic TMCs tools that emulate the efficiency and specificity of natural metalloenzymes is a rewarding yet challenging endeavor. Here, we highlight the potential of molecularly imprinted enzyme mimics (MIEs) containing a Cu center and specific substrate binding domain, for conducing dimethylpropargyloxycarbonyl (DmProc) cleavage reactions within cells. Our studies reveal that the Cu-MIEs act as highly specific guides, precisely catalyzing target substrates, even in glutathione (GSH)-rich cellular environments. By adapting templates similar to the target substrates, we evolved Cu-MIEs activity to a high level and provided a method to broaden its scope to other unique substrates. This system was applied to a thyroid hormone (T3)-responsive gene switch model, inducing firefly luciferase expression by T3 in cells. This approach verifies that MIEs effectively rescue DmProc-bearing T3 prodrugs and seamlessly integrating themself into cellular biocatalytic networks.

Targeting the GTPase RAN by liposome delivery for tackling cancer stemness-emanated therapeutic resistance.

Cancer therapeutic resistance as a common hallmark of cancer is often responsible for treatment failure and poor patient survival. Cancer stem-like cells (CSCs) are one of the main contributors to therapeutic resistance, cancer relapse and metastasis. Through screening from our in-house library of natural products, we found polyphyllin II (PPII) as a potent anti-CSC compound for triple-negative breast cancer (TNBC). To enhance anti-CSC selectivity and improve druggability of PPII, we leverage the liposome-mediated delivery technique for increasing solubility of PPII, and more significantly, attaining broader therapeutic window. Liposomal PPII demonstrates its marked potency to inhibit tumor growth, post-surgical recurrence and metastasis compared to commercial liposomal chemotherapeutics in the mouse models of CSC-enriched TNBC tumor. We further identify PPII as an inhibitor of the Ras-related nuclear (RAN) protein whose upregulated expression is correlated with poor clinical outcomes. The direct binding of PPII to RAN reduces TNBC stemness, thereby suppressing tumor progression. Our work offers a significance from drug discovery to drug delivery benefiting from liposome technique for targeted treatment of high-stemness tumor.

Transition Metal Ru(II) Catalysts Immobilized Nanoreactors for Conditional Bioorthogonal Catalysis in Cells.

Employing transition metal catalysts (TMCs) to perform bioorthogonal activation of prodrugs and pro-fluorophores in biological systems, particularly in a conditional fashion, remains a challenge. Here, we used a mesoporous organosilica nanoscaffold (RuMSN), which localizes Ru(II) conjugates on the pore wall, enabling the biorthogonal photoreduction reactions of azide groups. Due to easily adjustable surface charges and pore diameter, this efficiently engineering RuMSN catalyst, with abundant active sites on the inner pore well, could spontaneously repel or attract substrates with different molecular sizes and charges and thus ensure selective bioorthogonal catalysis. Depending on it, engineering RuMSN nanoreactors showed fascinating application scales from conditional bioorthogonal activation of prodrugs and pro-fluorophores in either intra- or extracellular localization to performing intracellular concurrent and tandem catalysis together with natural enzymes.

Lipid-polymer hybrid nanoparticle with cell-distinct drug release for treatment of stemness-derived resistant tumor.

Drug resistance presents one of the major causes for the failure of cancer chemotherapy. Cancer stem-like cells (CSCs), a population of self-renewal cells with high tumorigenicity and innate chemoresistance, can survive conventional chemotherapy and generate increased resistance. Here, we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent, all-trans retinoic acid and the chemotherapeutic drug, doxorubicin to overcome the CSC-associated chemoresistance. The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation. In the hypoxic CSCs, ATRA is released to induce differentiation of the CSCs, and in the differentiating CSCs with decreased chemoresistance, DOX is released upon elevation of reactive oxygen species to cause subsequent cell death. In the bulk tumor cells, the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect. This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism. We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.