Malignant tumor cells feature rapid metabolism and proliferation that need a large amount of energy to maintain these physiological activities. Blocking energy supply through mitochondria dysfunction is an alternative strategy but is hindered by the limited blockage efficacy and the repairation of cytoprotective autophagy. Herein, a novel kind of bull serum albumin (BSA)-coated rotenone (RO)-copper phosphate (CuPi) nanocompsites was prepared for tumor therapy through autophagy blockage-enhanced triphosadenine (ATP) supply interruption and lipid peroxidation (LPO) accumulation. When internalization by tumor cells, these formed BSA-RO-CuPi nanoparticles (NPs) degraded to release RO, Cu2+, and PO43−. RO acts on mitochondrial complex I and reduces the activity of Fe-S clusters, and Cu2+ is reduced into Cu+ by ferredoxin 1 (FDX1) to induce dihydrolipoamide S-acetyltransferase (DLAT) aggregation. Thus, mitochondria function is severely damaged to cut off ATP supply. Meanwhile, Cu2+ depletes glutathione (GSH) through a redox reaction and produces hydroxyl radicals through the Fenton-like reaction, inducing the generation of LPO. Importantly, PO43− weakens lysosomal acidity to disrupt the autophagy capacity of tumor cells, resulting in damage accumulation. In vivo data demonstrated that these developed BSA-RO-CuPi NPs show desirable antitumor capacity and emphasize the importance of mitochondria dysfunction in tumor treatment applications.

Metal iron plays exceedingly important roles in maintaining normal biological activities and is stored as an intracellular labile iron pool (LIP). Disturbing LIP balance to disorganize physiological reactions holds great promise in tumor therapy yet is still lacking exploration. Herein, a novel synergetic strategy was designed for tumor therapy with high efficacy and biocompatibility, which was realized through the metal-free poly(lactic-co-glycolic acid) (PLGA)-ethylenediaminetetraacetic acid (EDTA)-ebselen (EBS) nanocomposites. After degradation, EDTA chelates Fe2+ to deplete intracellular LIP, and EBS inactivates DMT1 protein to inhibit iron supplementation from extracellular regions. This LIP destruction causes the downregulation of iron-sulfur cluster levels, which compromises mitochondrial energy metabolism and arrests the cell cycle. Effective tumor elimination is achieved under PLGA-EDTA-EBS treatment with negligible side effects. This work presents an effective formulation for tumor therapy through a synergetic stock depletion and supply blockage strategy, thereby providing essential implications for the design of tumor therapeutic methods with minimal biosafety issues.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

The construction of novel photothermal agents (PTAs) with near-infrared (NIR) light-responsive capacity that can differentiate normal and abnormal tissues bidirectionally to minimize adverse effects of photothermal therapy (PTT) is of great importance yet a huge challenge. We are developing "Matthew Effect Photoimmunotheranostics (MEP)", demonstrated using an intelligent proton-driven enhanced nanoconverter (PEN) with self-refueling capacity by a facile polymerization method to form biocompatible photothermal agent polyaniline (PANI) with glucose oxidase (GOx) as the enhancer. PEN accumulates in the tumor region selectively after intravenous injection and GOx depletes glucose to re-establish the tumor microenvironment towards energy shortage and acidity aggravation, suppressing the expression of heat shock proteins to disturb the thermoresistance mechanism of tumor cells and promoting the proton-driven conversion of PANI to activated state synergistically. Strikingly, the PEN can differentiate normal and cancerous tissues bidirectionally with an "OFF-ON-OFF" mode to minimize adverse effects due to the enormous difference in glucose consumption between normal cells and tumor cells. PEN-mediated hyperthermia can induce immunogenic cell death. Under photoacoustic imaging and NIR-II light irradiation, PEN achieves tumor elimination with high specificity with synergistic mild hyperthermia/immune response by MEP. PEN-induced adaptive antitumor immunity is effective for eliminating distant tumors and suppressing tumor metastasis and recurrence.

Aim: The development of a collaborative strategy with improved efficacy holds great promise in tumor treatment. This study aims to develop an effective collaborative strategy based on functionalized mesoporous polydopamine (MPDA) nanocomposites for killing tumor cells. Methods: MPDA nanoparticles were synthesized and functionalized with camptothecin (CPT) payload and manganese dioxide (MnO2) coating to construct MPDA-CPT-MnO2 nanocomposites. Results: When uptaken by tumor cells, the nanocomposites can degrade to produce O2, release CPT, and generate manganese (Mn2+) under the stimulation of hydrogen peroxide (H2O2) and acid. The released CPT and Mn2+ can act as chemotherapeutic drug and Fenton-like agent, respectively. Abundant reactive oxygen species (ROS) are generated in 4T1 tumor cells through an Mn2+-mediated Fenton-like reaction. After that, the generated Mn4+ can react with glutathione (GSH) through redox reaction to produce Mn2+ and deplete GSH, disrupting the reducing capacity and benefiting the production of ROS in tumor cells. Under laser irradiation, the nanocomposites can generate hyperthermia to promote the production of ROS. Conclusions: The developed MPDA-CPT-MnO2 nanocomposites can kill tumor cells through collaborative chemo/photothermal/chemodynamic therapy (CDT).

Polydopamine (PDA)-based Fenton agents attract increasing attention in tumor photothermal-enhanced chemodynamic therapy (CDT) due to their good biocompatibility and excellent loading capacity. However, PDA tends to eliminate the Fenton reaction-generated hydroxyl radical (∙OH) by its strong reducibility, which is an intractable hinder to the efficacy of CDT that need to be solved. Herein, a kind of mesoporous PDA-gold-manganese dioxide (MPDA-Au-MnO2, MPAM) nanoplatform was constructed for photothermal-enhanced CDT against tumor through the reducibility weakening strategy. The reducibility of original MPDA is effectively weakened by the oxidation role of HAuCl4 and KMnO4 during the preparation process, reducing the ∙OH scavenging ability of MPDA and benefiting the production of ∙OH. The MnO2 shell could react with GSH to release Mn2+, acting as the Fenton-like agent to generate ∙OH. The exposed Au NPs can further deplete GSH through the Au-S bond interaction. MPDA acts as the photothermal agent to generate hyperthermia under laser irradiation. MPAM shows excellent intracellular GSH scavenging ability and enhanced ∙OH production ability. After intravenous injection, MPAM can significantly suppress the growth of tumors under laser irradiation, meanwhile showing good biosafety. The developed MPDA-based nanoplatform can not only display good potential in further tumor treatments but also provide meaningful enlightenment for developing high-performance PDA or MPDA-based nanoplatforms in CDT-related applications.

Elimination of tumor cells using carbonate nanomaterials with tumor microenvironment-responsive capacity has been explored as an effective strategy. However, their therapeutic outcomes are always compromised by the relatively low intratumoral accumulation and limited synthesis method. Herein, a novel kind of basic copper carbonate nanosheets was designed and prepared using a green synthesis method for photoacoustic imaging-guided tumor apoptosis and ferroptosis therapy. These nanosheets were synthesized with the assistance of dopamine and ammonium bicarbonate (NH4HCO3) and the loading of glucose oxidase (GOx). NH4HCO3 could not only provide an alkaline environment for the polymerization of dopamine but also supply carbonates for the growth of nanosheets. The formed nanosheets displayed good acid and near-infrared light responsiveness. After intercellular uptake, they could be degraded to release Cu2+ and GOx, generating hydroxyl radicals through a Cu+-mediated Fenton-like reaction, consuming glucose, up-regulating H2O2 levels, and down-regulating GSH levels. Tumor elimination could be achieved by hydroxyl radical-induced apoptosis and ferroptosis. More amusingly, this synthesis method can be extended to several kinds of mono-element and multi-element carbonate nanomaterials (e.g., Fe, Mn, and Co), showing great potential for further tumor theranostics.

Tumor-associated macrophages (TAMs)-mediated immunotherapy has attracted extensive attention in tumor elimination. However, the acidic tumor microenvironment (TME) severely limits the phenotype of TAMs to pro-tumoral M2 state, suppressing immune response efficacy against tumors. Herein, novel poly(acrylic acid) (PAA)-coated, doxorubicin (DOX)-loaded layered double hydroxide (LDH) nanosheets (NSs) were developed as deacidification agent to repolarize TAMs from pro-tumoral M2 to anti-tumoral M1 phenotype for tumor elimination through combined chemodynamic therapy and immunotherapy. When located in tumor regions, LDH-PAA@DOX NSs display good deacidification capacity to neutralize acidic TME, achieving the repolarization of TAMs to M1 phenotype and further activating CD8+ T cells. During the deacidification process, these NSs are acid-responsive and degrade to release Fe3+ and DOX. The former can be reduced to Fe2+ by intracellular glutathione, meanwhile disrupting the antioxidant defense system of tumor cells. The latter can damage tumor cells directly and further stimulate the production of hydrogen peroxide, providing abundant substrate for the Fenton reaction. Toxic hydroxyl radical is excessively produced through Fe2+-mediated Fenton reaction to cause intratumoral oxidative stress. In vivo data revealed that significant tumor elimination can be achieved under LDH-PAA@DOX treatment. This work not only provides a promising paradigm for neutralizing acidic TME using deacidification agent but also highlights the effectiveness of combined chemodynamic therapy and immunotherapy in tumor treatment.

Carbon-based nanomaterials are a kind of attractive photothermal agents (PTAs) for tumor photothermal therapy (PTT). However, their inherent fluorescent emission always compromises the photothermal conversion efficiency and is a huge obstruction that needs to be solved. Herein, a kind of hemoglobin (Hb)-decorated boron-carbon nanosheets (BC NSs) was designed and developed with catalytic ability and near-infrared II light-responsive performance for photoacoustic (PA) imaging guided synergistic tumor PTT/chemodynamic therapy (CDT). BC NSs were synthesized from biomass gelatin, coated with a polydopamine (PDA) layer, and decorated with Fenton agent Hb. The formed BC-PDA-Hb (BCPH) NSs had no fluorescent emission, high photothermal conversion performance (47.8% under 1064 nm laser irradiation), and excellent PA imaging capability. The Fe2+ carried in Hb can react with intratumoral overexpressed H2O2 to generate toxic hydroxyl radicals. In vitro and in vivo data revealed that BCPH NSs can achieve effective tumor elimination through synergistic PTT/CDT without detectable adverse effects on normal tissues. This work offers an effective strategy to develop carbon-based nanomedicines owning promoted photothermal performance and high biocompatibility for tumor theranostic applications.

Chemodynamic therapy (CDT) is a promising hydroxyl radical (•OH)-mediated tumor therapeutic method with desirable tumor specificity and minimal side effects. However, the efficiency of CDT is restricted by the pH condition, insufficient H2O2 level, and overexpressed reductive glutathione (GSH), making it challenging to solve these problems simultaneously to improve the efficacy of CDT. Herein, a kind of polyvinylpyrrolidone-stabilized, sorafenib-loaded copper peroxide (CuO2-PVP-SRF) nanoparticle (NPs) was designed and developed for enhanced CDT against tumor cells through the synergetic pH-independent Fenton-like, H2O2 self-supplying, and GSH depletion strategy. The prepared CuO2-PVP-SRF NPs can be uptaken by 4T1 cells to specifically release Cu2+, H2O2, and SRF under acidic conditions. The intracellular GSH can be depleted by SRF-induced system xc- dysfunction and Cu2+-participated redox reaction, causing the inactivation of GPX4 and generating Cu+. A great amount of •OH was produced in this reducing capacity-disrupted condition by the Cu+-mediated Fenton-like reaction, causing cell apoptosis and lipid hydroperoxide accumulation-induced ferroptosis. They display an excellent 4T1 cell killing outcome through the improved •OH production capacity. The CuO2-PVP-SRF NPs display elevated therapeutic efficiency of CDT and show good promise in further tumor treatment applications.

Synergistic apoptosis and ferroptosis strategy is quite promising for tumor treatment. Herein, a kind of polyacrylic acid-stabilized, carboxymethyl chitosan-coated, doxorubicin (DOX)-loaded copper phosphate nanoparticles (NPs) were prepared by a simple method for synergistic apoptosis and ferroptosis against tumor cells. The finally formed PAA-Cu-3(PO4)(2)-DOX-CMCS (PCPDC) NPs displayed suitable hydrodynamic size (208.7 nm) and surface charge. When uptaken by tumor cells, they were degraded under acidic circumstances, releasing DOX and Cu2+ ions. The released Cu2+ ions reacted with glutathione (GSH) to produce Cu+ ions and deplete GSH. Through Cu+ ions-mediated Fenton-like reaction, H2O2 can be converted to hydroxyl radical to produce lipid hydroperoxides. Furthermore, the depleted GSH down-regulated the expression of glutathione peroxidase 4 (GPX4) protein, promoting the accumulation of lipid hydroperoxides to enhance ferroptosis. The released DOX can effectively induce apoptosis in tumor cells. These developed Cu-3(PO4)(2)-based nanomaterials can kill tumor cells effectively through the synergistic apoptosis and ferroptosis strategy.