Photothermal
treatment (PTT) involving a combination of therapeutic
modalities recently emerged as an efficient alternative for combating
biofilm. However, PTT-related local high temperature may destroy the
surrounding healthy tissues. Herein, we present an all-in-one phototherapeutic
nanoplatform consisting of l-arginine (l-Arg), indocyanine
green (ICG), and mesoporous polydopamine (MPDA), namely, AI-MPDA,
to eliminate the already-formed biofilm. The fabrication process included
surface modification of MPDA with l-Arg and further adsorption
of ICG via π–π stacking. Under
near-infrared (NIR) exposure, AI-MPDA not only generated heat but
also produced reactive oxygen species, causing a cascade catalysis
of l-Arg to release nitric oxide (NO). Under NIR irradiation,
biofilm elimination was attributed to the NO-enhanced photodynamic
therapy and low-temperature PTT (≤45 °C). Notably, the
NIR-triggered all-in-one strategy resulted in severe destruction of
bacterial membranes. The phototherapeutic AI-MPDA also displayed good
cytocompatibility. NIR-irradiated AI-MPDA nanoparticles not only prevented
bacterial colonization but also realized a rapid recovery of infected
wounds. More importantly, the all-in-one phototherapeutic platform
displayed effective biofilm elimination with an efficiency of around
100% in a abscess formation model. Overall, this low-temperature phototherapeutic
platform provides a reliable tool for combating already-formed biofilms
in clinical applications.
As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8 + T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into "hot" tumors and inhibit the tumor growth with high efficiency in vivo.
Ferroptosis
is a recently discovered route of regulated cell death
that offers the opportunities for the treatment of chemotherapy-resistant
tumor indications, but its efficacy can be affected by the glutathione
peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant
mechanisms, posing significant challenges for its clinical translation.
In this study, we report a Cu-tetra(4-carboxyphenyl)porphyrin chloride(Fe(III))
(Cu-TCPP(Fe)) metal organic framework (MOF)-based nanosystem for the
efficient incorporation of Au nanoparticles (NPs) and RSL3, which
can demonstrate enzyme-like activities to universally suppress the
antiferroptotic pathways in tumor cells for amplifying ferroptotic
damage. Herein, Cu-TCPP(Fe) MOF nanosheets were integrated with Au
NPs via in situ nucleation and loaded with RSL3 via π–π stacking, which were eventually
modified with polyethylene glycol (PEG) and iRGD for tumor-targeted
drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like
activities for efficient glucose depletion, thus disrupting the pentose
phosphate pathway to impede reduced glutathione (GSH) biosynthesis
and prevent the recycling of coenzyme Q10 (CoQ10) to CoQ10H2, while
Cu species can oxidize GSH into oxidized glutathione (GSSG). These
nanocatalytic activities can lead to the simultaneous inhibition of
the GPX4/GSH and FSP1/CoQ10H2 pathways and cooperate with the GPX4-deactivating
function of RSL3 to cause pronounced ferroptotic damage, thereby providing
a strong rationale for the application of ferroptosis therapy in the
clinic.
Clinically, inhibition of both bacterial infection and excessive inflammation is a crucial step for improved wound treatments. Herein, the fabrication of near‐infrared‐light (NIR)‐activatable deoxyribonuclease (DNase)–carbon monoxide (CO)@mesoporous polydopamine nanoparticles (MPDA NPs) is demonstrated for efficient elimination of methicillin‐resistant Staphylococcus aureus (MRSA) biofilms and the following anti‐inflammatory activity. Specifically, thermosensitive CO‐gas‐releasing donors (CO releasing molecules, FeCO) are first encapsulated into MPDA NPs, followed by covalently immobilizing deoxyribonuclease I (DNase I) on the surfaces of MPDA NPs. DNase I can degrade the extracellular DNA in biofilms, which site specifically destroys the compactness of the biofilms. With NIR irradiation, DNase–CO@MPDA NPs display great photothermal ability, and further trigger on‐demand delivery of bactericidal CO gas that can adequately permeate the impaired biofilms. Eventually, they achieve effective MRSA biofilm elimination in virtue of the synergistic effects of both DNase I participation and CO‐gas‐potentiated photothermal therapy. Importantly, the inflammatory responses of DNase–CO@MPDA NPs and NIR‐treated wounds are simultaneously alleviated owing to the anti‐inflammatory features of released CO. Finally, NIR‐activatable DNase–CO@MPDA NPs accelerate the healing process of MRSA‐biofilm‐infected cutaneous wounds. Taken together, this phototherapeutic strategy displays great therapeutic potential in treating the formidable clinical problems caused by MRSA biofilms and the accompanying inflammation.
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