Bioorthogonal catalysis mediated by abiotic transition metal catalysts (TMCs) is emerging as a momentum-gathering strategy for in situ generation of therapeutics. However, the unpredictable leakage and deposition of TMCs in living systems easily lead to nonspecific exposure of catalysts and concomitant off-target prodrug activation. Herein, we propose an enzyme-gated bioorthogonal catalytic nanoreactor constructed from hyaluronic acid (HA)-coated dendritic mesoporous silica nanoparticles (DMSNs), where the latter serves as a host for robustly immobilizing organometallic Ru(II) catalysts via covalent interactions. The covalent immobilization of catalysts within the nanoscaffold effectively avoids nonspecific metal leakage under biological conditions. Importantly, the grafted HA not only acts as a "gatekeeper" preventing unintended catalyst exposure in nontargeted tissues but also acts as a ligand targeting CD44 overexpressed cancer cells. Upon receptor-mediated endocytosis into tumor cells, HA is degraded by the overexpressed hyaluronidase-1, leading to the channel opening of the nanoreactors and hence gaining the accessibility of Ru(II) complexes to prodrugs. The therapeutic potency of this enzyme-gated nanoreactor in mediating site-specific activation of caged prodrugs was systematically demonstrated both in cellular settings and in tumor-bearing murine models. This enzyme-gated strategy enhances the efficacy of localized treatment while avoiding off-target prodrug activation, paving the way for advancing bioorthogonal catalysis for disease management in a safe and effective way.

Androgenetic alopecia (AGA) is a chronic and progressive form of hair loss characterized by vascular degeneration in the perifollicular microenvironment, leading to cell apoptosis and eventual loss of hair follicles (HFs). Traditional therapeutic formulations, such as Minoxidil (MXD) tincture, have limitations in reshaping the perifollicular microenvironment and exhibit limited effectiveness. Here, we report a multi-synergistic therapeutic platform for high-performance hair regeneration therapy. The platform combines microneedle (MN) patches loaded with MXD-encapsulated nanostructured lipid carriers (MXD-NLC-MNs) and cold atmospheric plasma (CAP). The MNs’ mechanical strength enables efficient transdermal delivery of MXD to the targeted dermal papilla cells, promoting cell proliferation. Furthermore, in collaboration with MXD, the mechanical stimulation exerted by MN application synergistically upregulates the expression of vascular endothelial growth factor, leading to neoangiogenesis. Meanwhile, the transient microchannels in the skin created by MNs facilitate the transdermal delivery of CAP-generated nitric oxide (NO) to the sites of HF lesions, whereby the synergistic interaction between MXD and NO boosts perifollicular vasodilation. Consequently, the perifollicular microenvironment can be effectively reshaped to accelerate hair regeneration in AGA murine models. This multi-synergistic combination therapy strategy would hold great promise for effectively treating AGA and promoting hair regrowth.

The abundant intracellular glutathione (GSH) in cancer cells severely undermines the therapeutic efficacy of different treatments due to their role in protecting cancer cells from the associated oxidative stress. Developing a highly integrated system to consume GSH would help to improve the therapeutic outcomes. In this study, supramolecular prodrug self-assemblies (SPSAs) with IR825 loaded inside were developed to consume GSH via two-pronged pathways while augmenting the therapeutic potency of chemo/photothermal treatment. SPSAs were prepared using water-soluble pillar[6]arene (WP[6]) as host units and H₂O₂-responsive nitrogen mustard prodrug, chlorambucil-(phenylboronic acid pinacol ester) conjugates (Cb-BE), as the guests. When SPSAs were internalized by cancer cells, the generation of quinone methide (QM) from Cb-BE and singlet oxygen (¹O₂) from irradiation-activated IR825 could consume GSH in a concerted way. As such, the therapeutic efficacies of the released chlorambucil and the accompanied hyperthermia were augmented toward synergistically inhibiting tumor growth.

The ascendant danger of bacterial infections has resulted in an urgent requirement for developing new antibacterial approaches. Recently, nitric oxide (NO) has shown a broad-spectrum antimicrobial activity while avoiding resistance. However, achieving effective NO-based antibacterial therapies remains challenging, mired by the safety concerns of NO donor, residual toxicity by the ingredients, or complicated procedures. Herein, a self-activated NO-releasing hydrogel depot is fabricated by Ca²⁺-crosslinked sodium alginate doped with CaO₂ nanoparticles, L-arginine, and oxidized mesoporous carbon nanoparticles (OMCN) for photothermal enhanced bacteria killing. The locally concentrated H₂O₂, generated from the reaction of CaO₂ nanoparticles and water, could oxidize L-arginine to release NO. Meanwhile, benefiting from the remarkable photothermal effect of OMCN, the hybrid hydrogel possesses a synergistic sterilization behavior in combating both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacteria in vitro. Moreover, the dual therapeutic hydrogel displays high efficiency in treatment of bacteria-infected mice with back wound model while showing no distinct toxicity. In addition, the restricted environment of hydrogel makes it easy to remove all the components from the infected wound, alleviating possible side effects from exogenous H₂O₂. As such, the designed NO-synergistic photothermal hydrogel provides a promising strategy for treating bacterial infections.