MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1 -weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

Unleashing the Power of PET-RAFT Polymerization: Journey from Porphyrin-Based Photocatalysts to Combinatorial Technologies and Advanced Bioapplications.

The emergence of photoinduced energy/electron transfer-reversible addition-fragmentation chain transfer polymerization (PET-RAFT) not only revolutionized the field of photopolymerization but also accelerated the development of porphyrin-based photocatalysts and their analogues. The continual expansion of the monomer family compatible with PET-RAFT polymerization enhances the range of light radiation that can be harnessed, providing increased flexibility in polymerization processes. Furthermore, the versatility of PET-RAFT polymerization extends beyond its inherent capabilities, enabling its integration with various technologies in diverse fields. This integration holds considerable promise for the advancement of biomaterials with satisfactory bioapplications. As researchers delve deeper into the possibilities afforded by PET-RAFT polymerization, the collaborative efforts of individuals from diverse disciplines will prove invaluable in unleashing its full potential. This Review presents a concise introduction to the fundamental principles of PET-RAFT, outlines the progress in photocatalyst development, highlights its primary applications, and offers insights for future advancements in this technique, paving the way for exciting innovations and applications.

Ultrasmall Self-Cascade AuNP@FeS Nanozyme for H2S-Amplified Ferroptosis Therapy.

Recently, nanozymes with peroxidase (POD)-like activity have shown great promise for ferroptosis-based tumor therapy, which are capable of transforming hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH). However, the unsatisfactory therapeutic performance of nanozymes due to insufficient endogenous H2O2 and acidity at tumor sites has always been a conundrum. Herein, an ultrasmall gold (Au) @ ferrous sulfide (FeS) cascade nanozyme (AuNP@FeS) with H2S-releasing ability constructed with an Au nanoparticle (AuNP) and an FeS nanoparticle (FeSNP) is designed to increase the H2O2 level and acidity in tumor cells via the collaboration between cascade reactions of AuNP@FeS and the biological effects of released H2S, achieving enhanced •OH generation as well as effective ferroptosis for tumor therapy. The cascade reaction in tumor cells is activated by the glucose oxidase (GOD)-like activity of AuNP in AuNP@FeS to catalyze intratumoral glucose into H2O2 and gluconic acid; meanwhile, the released H2S from AuNP@FeS reduces H2O2 consumption by inhibiting intracellular catalase (CAT) activity and promotes lactic acid accumulation. The two pathways synergistically boost H2O2 and acidity in tumor cells, thus inducing a cascade to generate abundant •OH by catalyzing H2O2 through the POD-like activity of FeS in AuNP@FeS and ultimately causing amplified ferroptosis. In vitro and in vivo experiments demonstrated that AuNP@FeS presents a superior tumor therapeutic effect compared to that of AuNP or FeS alone. This strategy represents a simple but powerful method to amplify ferroptosis with H2S-releasing cascade nanozymes and will pave a new way for the development of tumor therapy.

A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy.

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe2+-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe2+-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe2+-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe2+-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe2+-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8+ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-ß and IFN-γ.

Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy.

Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H2O2) content, and insufficient acidity in the tumor environment (TME), which are unfavorable for reactive oxygen species (ROS) generation based on Fenton or Fenton-like reactions. The glutathione (GSH) overexpression in TME can scavenge ROS and abate the FT performance. In this study, a strategy of ROS storm generation specifically initiated by the TME and our developed nanoplatforms (TAF-HMON-CuP@PPDG) is proposed for high-performance FT of tumors. The GSH in the TME initiates HMON degradation, resulting in tamoxifen (TAF) and copper peroxide (CuP) release from TAF3-HMON-CuP3@PPDG. The released TAF leads to enhanced acidification within tumor cells, which reacts with the released CuP producing Cu2+ and H2O2. The Fenton-like reaction between Cu2+ and H2O2 generates ROS and Cu+, and that between Cu+ and H2O2 generates ROS and Cu2+, forming a cyclic catalysis effect. Cu2+ reacts with GSH to generate Cu+ and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu+ and H2O2. The GSH consumption decreases the glutathione peroxidase 4 (GPX4) expression. All of the above reactions generate a ROS storm in tumor cells for high-performance FT, which is demonstrated in cancer cells and tumor-bearing mice.

A Strategy of Fenton Reaction Cycloacceleration for High-Performance Ferroptosis Therapy Initiated by Tumor Microenvironment Remodeling.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2 O2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high-performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), ß-lapachon (LAP), Fe3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI-guided high-performance ferroptosis therapy of tumors.

Nanoprobes for Tumor Theranostics.

This Special Issue of Biosensors, entitled "Nanoprobes for Tumor Theranostics", aims to report the research progress of using nanoprobes for the diagnosis and therapy of tumors, and promote their applications [...].

Dual-generation dendritic mesoporous silica nanoparticles for co-delivery and kinetically sequential drug release.

Although multi-drug synergetic therapy is increasingly important in clinical application, sophisticated delivery systems with the ability to deliver multiple drugs and realize sequential release with independently tunable kinetics at different stages are highly desirable. In this study, a dual-generation mesoporous silica nanoparticle (DAMSN) with three-dimensional dendrimer-like structure as an adaptable dual drug delivery system is developed. The DAMSN was synthesized via a heterogeneous interfacial reaction and was of uniformly spherical morphology (150-170 nm) with dendritic structures and hierarchical pores (inner pore, 3.5 nm; outer pore, 8.3 nm). And the inner generation of DAMSN was modified with 3-aminopropyltriethoxysilane (APTMS). The IBU and BSA as model drugs were loaded into the inner generation via covalent conjugation and the outer generation by electrostatic adsorption, respectively. Intriguingly, DAMSN underwent a rapid bio-degradation for about 4 days, partly due to its center-radial dendritic channel structure. The release results showed that IBU was of a typical two-phase release profile with almost zero release in the first 12 h and more sustained release for the following 88 h, while BSA was sustained over a long period of 100 h. Notably, the release behaviors of both drugs can be independently tailored by changing the intrinsic properties of the DAMSN. In addition, DAMSN exhibited good bio-compatibility. These results indicated that the dual-generation, dendrimer-like MSN structure could spatiotemporally present different drugs to realize sequential drug release, and has potential use in the field of tissue engineering and regenerative medicine.

pH-Responsive Fe3O4 Nanopartilces-Capped Mesoporous Silica Supports for Protein Delivery.

Delivery of proteins and peptides with excellent bioactivity and controlled release still is a great challenge nowadays. In this study, a pH-responsive delivery system obtained by anchoring 8-nm Fe3O4 nanoparticles (NPs) onto SBA-15 supports with a particle diameter in the range of 0.6-1 µm and a pore size of 6.2 nm was synthesized and investigated. The pH-stimulative response is based on the interaction between the tris(aminomethyl)ethane (TAE) groups anchored onto the pore outlet of mesoporous silica scaffolds and the carboxybenzaldehyde (CBA) groups coated on the Fe3O4 NPs, which can lead to a rapid release under the acid condition (pH = 5) and a zero release with the increase of pH value (pH = 7.4). With BMP-2 as a model protein, this Fe3O4 nanopartilces-capped mesoporous silica showed a rapid response to the change of pH for protein delivery. Furthermore, the released BMP-2 could still maintain its bioactivity and induce the osteoblast differentiation of BMSCs. Besides, the magnetic orientation mainly attributes to the Fe3O4 NPs served as the nanocaps. The excellent bio-compatibility is demonstrated by the MTT assay on BMSCs model cells. These results show that Fe3O4 NPs-capped SBA-15 materials have an effective load for large molecule size proteins, such as BMP-2, and show an excellent applied prospect in pH-responsive controlled release system.

A proton-responsive ensemble using mesocellular foam supports capped with N,O-carboxymethyl chitosan for controlled release of bioactive proteins.

A novel pH-responsive mesocellular foam-based nanocarrier was fabricated by the covalent assembly of a water-soluble N,O-carboxymethyl chitosan via the crosslinking of GPTMS. The delivery systems show excellent protein loading with programmable release in an acid environment. Moreover, the released proteins still preserve their conformational and biological activity.

A dual-delivery system of pH-responsive chitosan-functionalized mesoporous silica nanoparticles bearing BMP-2 and dexamethasone for enhanced bone regeneration.

Bone morphogenetic protein-2 (BMP-2) is considered one of the most effective and extensively used growth factors to induce osteoblast differentiation and accelerate bone regeneration. Dexamethasone (Dex) with suitable dosage can enhance BMP-2-induced osteoblast differentiation. To strengthen this synergistic osteoinductive effect, a pH-responsive chitosan-functionalized mesoporous silica nanoparticle (chi-MSN) ensemble was fabricated for dual-delivery of BMP-2 and Dex. The MSNs are prepared by a CTAB-templated sol-gel method, and further coated by chitosan via the crosslinking of glycidoxypropyltrimethoxysilane (GPTMS). The small Dex is encapsulated in the mesopores and the large BMP-2 is incorporated into the chitosan coating. These chi-MSNs can quickly release BMP-2 in a bioactive form and can then be efficiently endocytosed and further realize a controlled release of Dex with the decreased pH value into/in cells. With the synergistic action of BMP-2 and Dex outside and inside the cell, this dual hybrid delivery system can significantly stimulate osteoblast differentiation and bone regeneration in vitro and in vivo. Together, this dual-delivery strategy for osteogenic protein delivery may enhance clinical outcomes by retaining the bioactivity and optimizing the release mode of the drug/protein.