Zhiguo Gao

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.

We report a pH-triggered cascade nanoreactor that could locally boost oxidative stress via increasing ˙OH generation and GSH depletion, showing great potential in tumor-specific nanocatalytic therapy.

We reported the synthesis of a tris(triazolylmethyl)amine (TTA)-bridged organosilane, functioning as Cu(I)-stabilizing ligands, and the installation of this building block into the backbone of mesoporous organosilica nanoparticles (TTASi) by a sol–gel way. Upon coordinating with Cu(I), the mesoporous Cu^I-TTASi, with a restricted metal active center inside the pore, functions as a molecular-sieve-typed nanoreactor to efficiently perform Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reactions on small-molecule substrates but fails to work on macromolecules larger than the pore diameter. As a proof of concept, we witnessed the advantages of selective nanoreactors in screening protein substrates for small molecules. Also, the robust Cu^I-TTASi could be implanted into the body of animal models including zebrafish and mice as biorthogonal catalysts without apparent toxicity, extending its utilization in vivo ranging from fluorescent labeling to in situ drug synthesis.

Cutting off the energy supply by glucose oxidase (GOx) to starve cancer cells has been a feasible and efficient oncotherapy strategy. The employment of GOx effectively starves tumor cells by aerobic hydrolysis of glucose, and in turn reconstitutes the tumor microenvironment (TME) by strengthening the abnormality (including the decrease of the pH, the increase of hypoxia and toxic hydrogen peroxide). On this basis, we designed and fabricated a GOx-conjugated yolk-shell [email protected] nanoframes with Ag NPs and GOx-conjugated mesoporous silica as yolk and shell respectively, to make full use of changes in TME the GOx brings. Specially, the lower pH and the generation of H2O2 could accelerate the transform of Ag nanoparticles to poisonous Ag ions. At the same time, the anabatic hypoxia condition in turn activated chemotherapy drug tirapazamine (TPZ) to play a chemotherapeutic effect, thereby achieving effective multimodality therapy (Chemo/Starvation and metal ions). The drug release experiment in vitro demonstrated that the GOx is the key of the nano carriers which can activate the whole system. Its excellent cellular uptake performances were obtained by Confocal Laser Scanning Microscope (CLSM). In addition, its superb cancer killing effect has been confirmed by the cytotoxicity and apoptosis experiments. These results indicated that the drug delivery system achieved the cascade cancer killing progress in situ and synergistic chemo/metal ions/starvation therapy, which have a bright prospect for treating cancer.

Dendritic mesoporous silica nanoparticles represent a new biomedical application platform due to their special central radial pore structure for the loading of drugs and functional modification. Herein, we report functionalized dendritic mesoporous organosilica nanoparticles (DMONs), a pH-triggered Fenton reaction generator (TA/[email protected]@DMONs), incorporating natural glucose oxidase (GOD) in the DMONs with tannic acid (TA) grafted using Fe3+ on the surface, designed and constructed for efficient tumor ablation with self-supplied H2O2 and accelerated conversion of Fe3+/Fe2+ by TA. In view of the deficiency of endogenous H2O2, self-supply through the TA/[email protected]@DMONs platform represented a high-yielding source of peroxygen. Furthermore, the production of Fe2+ induced by TA greatly improved the efficiency of the Fenton reaction resulting in significant tumor inhibition. This new design represents as novel paradigm for the development of autocatalytic Fenton nanosystems for effective treatment of tumors.

Recent studies have suggested that the anticancer activity of disulfiram (DSF, an FDA-approved alcohol-abuse drug) is Cu-dependent. Low system toxicity and explicit pharmacokinetic characteristics of DSF necessitate safe and effective Cu supplementation in local lesion for further applications. Herein, we presented a new conceptual ‘nanosized coordination transport’ strategy of Cu(II) that was realized in porphyrin-based metal–organic frameworks, Sm-TCPP, with strong binding ability to Cu(II) due to their coordination interactions. Sm-TCPP(Cu) was coated by hyaluronic acid (HA) that termed by Sm-TCPP(Cu)@HA, acting as ‘beneficial horse’ to target the tumor-localized HA receptor (CD44), thus liberating Cu(II) ions in cellular overexpressed reductants. The CD44-mediated Cu(II) accumulation efficiency of Sm-TCPP(Cu)@HA was benchmarked in vitro and vivo against the free TCPP (Cu) via ICP-MS analysis. More importantly, the sensitization effects of Sm-TCPP(Cu)@HA on the anticancer activity of DSF were demonstrated in vivo and in vitro. This study offered a new class of targeted Cu supplements to sensitize DSF for the effective treatment of cancer and established a versatile methodology for constructing a safe and specific delivery of metal ions within living organisms.

Photodynamic Therapy (PDT) as a noninvasive therapy mode has attracted considerable attention in the field of oncotherapy. However, the PDT efficacy is restricted either by tumor hypoxia environment or the inherent properties of photosensitizers (PSs) including bad water solution, photobleaching, and easy aggregation. Herein, we designed and synthesized a new 2D metal-organic framework Sm-TCPP nanosheets by assembling transition metal ion (Sm3+) and PSs (TCPP), on which the catalase (CAT)-mimicking platinum nanozyme were then in situ grown for sufficient oxygen supply during PDT. The prepared Sm-TCPP with nanoplate morphology (~100 nm in diameter) and ultrathin thickness (<10 nm) showed significantly enhanced 1O2 generation capacity due to the improved physicochemical property and the enhanced intersystem crossing from heavy Sm nodes. More importantly, the CAT-mimicking Pt nanozyme on the Sm-TCPP nanosheets could effectively convert over-expressed H2O2 in tumor microenvironment (TME) into O2 to relieve tumor hypoxia. Further, triphenylphosphine (TPP) molecule was introduced to Sm-TCPP-Pt for an mitochondria-targeting and O2 self-supply PDT system. The experimental results in vitro and in vivo based on MCF-7 breast cancer model revealed that Sm-TCPP-Pt/TPP could relieve tumor hypoxia, and the generated ROS nearby intracellular mitochondria significantly induced cell apoptosis. This study offers an engineering strategy to integrate 2D PSs-based MOF and nanozymes into a nanoplatform to surmount the pitfalls of traditional PDT.

The hypoxia-responsive-Azo–BSA functionalized biomimetic nanoreactor achieved a sustaining and intensive Fenton reaction accelerated by not only sustained Fe ²⁺ and H ₂ O ₂ supply but also low pH and photothermal stimulation.

The efficiency of photosensitizers in tumor photodynamic therapy (PDT) often compromises their poor water solubility, low extinction coefficients, photobleaching, and dissatisfactory reactive oxygen species (ROS) generation efficiency. Herein, a nanoscale 2D metal–organic framework, Sm-H₂TCPP nanosheets, was first synthesized by Sm³⁺-driven coordination with a porphyrin derivative (tetrakis(4-carboxyphenyl)porphyrin (H₂TCPP)) for highly effective PDT of breast cancer. The prepared Sm-H₂TCPP possessed nanoplate morphology with ultrathin thickness at the sub-10 nm level and an ultrasmall plane size at the sub-100 nm level. Compared with free H₂TCPP, the prominent ROS generation capacity of the well-defined Sm-H₂TCPP nanosheets is mainly attributed to their improved physicochemical properties and the enhanced intersystem crossing caused by heavy Sm nodes. The significantly improved PDT efficacy of the Sm-H₂TCPP nanosheets was further investigated in vitro and in vivo based on the MCF-7 breast cancer model. It is envisaged that the Sm-H₂TCPP nanosheets will offer a new avenue for the development of a new class of potential PDT agents.

Up to now, ferroptotic therapeutic strategies remain simplex, though ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on [email protected] nanocomposites (HMCM) for efficient tumor ablation. The HMCM possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxides (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis, due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated the HMCM exhibited superior anticancer effect in human breast cancer models, and the combination therapeutic system afford the next generation of ferroptotic therapy for combatting malignant tumor.