Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited.

BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i).

Sponge-like nano-system suppresses tumor recurrence and metastasis by restraining myeloid-derived suppressor cells-mediated immunosuppression and formation of pre-metastatic niche.

Tumor recurrence and metastasis still greatly limit the therapeutic efficiency on the majority of postoperative clinical cases. With the aim to realize more powerful treatment outcomes on postoperative malignant tumors, a sponge-like neutrophil membrane-coated nano-system (NM/PPcDG/D) was fabricated to inhibit tumor recurrence and metastasis by inhibiting the recruitment and functions of myeloid-derived suppressor cell (MDSCs), which reinforced anti-tumor immunity and also suppressed pulmonary metastasis by inhibiting the formation of pre-metastatic niche (PMN). Firstly, PPcDG/D nanoparticles (NPs) were formulated by the self-assembling and crosslinking of synthesized redox-responsive polymer (PPDG) with doxorubicin (DOX) loading in the nanocore (PPcDG/D), followed by coating with activated neutrophils membrane to fabricate biomimetic NM/PPcDG/D.

Micellar nanoparticles inhibit breast cancer and pulmonary metastasis by modulating the recruitment and depletion of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are notorious for their pathological characteristics of immunosuppression and their promoting effect on cancers. They can induce the formation of pre-metastatic niche (PMN) characterized by inflammation, immunosuppression and vascular leakage, and promote pulmonary metastasis of breast cancer. Herein, a tumor targeting c(RGDfk) peptide modified low molecular-weight-heparin-all-trans-retinoic-acid (LMWH-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) and immune adjuvant α-galactosylceramide (αGC) (RLA/DOX/αGC NP) was developed.

Micellar nanoparticles inhibit the postoperative inflammation, recurrence and pulmonary metastasis of 4T1 breast cancer by blocking NF-κB pathway and promoting MDSCs depletion.

The progression of breast cancer can stimulate the production of myeloid-derived suppressor cells (MDSCs). These cells with significant immunosuppressive activity play a key role in promoting the formation of pulmonary inflammatory and immunosuppressive microenvironment, namely pre-metastatic niche (PMN). Surgical resection of tumors often leads to strong inflammatory reactions, and the produced circulating tumor cells (CTCs) can implant into PMN to promote the recurrence and pulmonary metastasis of breast cancer.

Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward loops.

Inflammatory feed-forward loops including the steps of "inflammatory cell recruitment", "inflammatory signaling pathway activation" and "inflammatory factor production" are essential in the development of breast cancer and its metastasis. Herein, a doxorubicin-loaded micellar low-molecular-weight-heparin-astaxanthin nanoparticle (LMWH-AST/DOX, LA/DOX NP) was developed. The hydrophilic LMWH could decrease the recruitment of neutrophils in liver and myeloid-derived suppressor cells (MDSCs) in lung and tumor through P-selectin blockage.

Redox-responsive nanoassembly restrained myeloid-derived suppressor cells recruitment through autophagy-involved lactate dehydrogenase A silencing for enhanced cancer immunochemotherapy.

Myeloid-derived suppressor cells (MDSCs) are the chief accomplices for assisting tumor's survival and suppressing anti-tumor immunity, which can be recruited by tumor-derived cytokines, such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). The plentiful lactate dehydrogenase A (LDHA) in glycolysis is usually accompanied by abundant tumor-derived G-CSF and GM-CSF, further promoting MDSCs recruitment and immunosuppression. Herein, with the aim to achieve powerful anti-tumor immunity, an immunochemotherapy regimen basing on a redox-responsive nanoassembly (R-mPDV/PDV/DOX/siL) is developed, which integrates the combined strategy of restraining cytokines-mediated MDSCs recruitment through LDHA silencing and reinforcing tumor immunogenicity through anthracycline (DOX)-elicited immunogenic cell death (ICD) effects.

Self-promoted Albumin-Based Nanoparticles for Combination Therapy against Metastatic Breast Cancer via a Hyperthermia-Induced "Platelet Bridge".

It has been a great challenge to simultaneously inhibit the outgrowth of both the primary tumor and metastasis in metastatic cancer treatment. Substantial studies have evidenced that the interaction of platelets and cancer cells supports tumor metastasis, and platelets are considered to have metastasis-targeting property. Inspired by injury-targeting and metastasis-targeting properties of platelets, we constructed a photothermal therapy strategy with activated platelet-targeting albumin-based nanoparticles, PSN-HSA-PTX-IR780, to amplify drug delivery in the primary tumor at mild temperatures and simultaneously inhibit metastasis via a "platelet bridge".

Phenylboronic acid modified nanoparticles simultaneously target pancreatic cancer and its metastasis and alleviate immunosuppression.

Pancreatic ductal adenocarcinoma is one of the most lethal malignant tumors, its drug resistance, immunosuppression and metastasis makes the traditional chemotherapy and immunotherapy inefficient. Here we confirmed a 3-aminophenylboronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) could inhibit orthotopic pancreatic tumor and its spontaneous metastases. The small particle size and high affinity of PBA to sialic acid residue (SA) made PLT/PTX NPs significantly targeted and accumulated in both pancreatic tumor tissues and metastases.

Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils.

Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs).

Rapid pH-responsive self-disintegrating nanoassemblies balance tumor accumulation and penetration for enhanced anti-breast cancer therapy.

The dilemma of tumor accumulation and deep penetration has always been a barrier in antitumor therapy. Stimuli-responsive size changeable drug delivery systems provide possible solutions. Nevertheless, the low size-shrinkage efficiency limited the antitumor effects.

Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS.

Chemotherapy agents have been widely used for cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus, prodrug strategy was devised. Since some prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy.

On-Demand Autophagy Cascade Amplification Nanoparticles Precisely Enhanced Oxaliplatin-Induced Cancer Immunotherapy.

Chemoimmunotherapy-induced antitumor immune response is highly dependent on tumor autophagy. When tumor cells are treated with chemoimmunotherapy, timely overactivated autophagy can not only lead more tumor cells to death, but also participate in the endogenous antigen presentation and immune stimulators secretion of dying cells, thus plays a vital role. However, timely and accurately overactivated tumor autophagy during chemoimmunotherapy is of great difficulty.

Autophagy inhibition changes the disposition of non-viral gene carriers during blood-brain barrier penetration and enhances TRAIL-induced apoptosis in brain metastatic tumor.

Non-viral gene delivery systems have proven to be a promising approach in the treatment of brain metastatic cancers but facing delivery difficulties. Due to the existence of blood-brain barrier, non-viral gene carriers must pass through brain capillary endothelial cells to accumulate at the brain tumor sites. However, during this process, most of them trap into brain capillary endothelial cells and fail to penetrate to the brain tumor sites.

Self-Delivery Micellar Nanoparticles Prevent Premetastatic Niche Formation by Interfering with the Early Recruitment and Vascular Destruction of Granulocytic Myeloid-Derived Suppressor Cells.

Distal metastases of tumors result from the interaction between "seeds" (circulating tumor cells, CTCs) and "soil" (premetastatic niche, PMN). Various strategies focus on CTC inhibition, but only a few strategies inhibit PMN formation. The main predisposition of PMN formation in melanoma lies in the pulmonary recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11bLy6G cells) induced by tumors, which increase vascular permeability by secreting matrix metalloproteinase-9 (MMP-9) and result in immunosuppression by secreting interleukin-10 (IL-10) in premetastatic lungs.

Enhanced Melanoma-Targeted Therapy by "Fru-Blocked" Phenyboronic Acid-Modified Multiphase Antimetastatic Micellar Nanoparticles.

Metastasis remains the main driver of mortality in patients suffering from cancer because of the refractoriness resulting from the multi-phase metastatic cascade. Herein, a multifunctional self-delivering PBA-LMWH-TOS nanoparticle (PLT NP) is established that acts as both nanocarrier and anti-metastatic agent with effects on most hematogenous metastases of cancers. The hydrophilic segment (low molecular weight heparin, LMWH) inhibits the interactions between tumor cells and platelets.

Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8 T cells.

Cholesterol facilitated the formation of T cell receptor on cytotoxic CD8 T lymphocytes (CTLs). However, the activation of CD8 T cells always resulted in the upregulation of acetyl-CoA acetyltransferase-1 (ACAT-1) and enhanced the esterification of cholesterol. To relieve the suppression on CD8 T cells, an ACAT-1 inhibitor avasimibe was combined with chemo-immunotherapy.

A size switchable nanoplatform for targeting the tumor microenvironment and deep tumor penetration.

The complex tumor microenvironment (TME) in solid tumors forms physiological barriers to the efficient delivery of nanomedicine, leading to limited therapeutic efficacy. Herein, to overcome these physiological barriers and improve the therapeutic effect, we constructed a novel size-adjustable nanoplatform for efficient drug delivery into solid tumors. The smart size-switchable nanoplatform (DGL/DOX@PP) was prepared by conjugating small dendrigraft poly-l-lysine (DGL) to poly(ethylene glycol)-poly(caprolactone) micelles via a matrix metalloproteinase 2 (MMP-2)-sensitive peptide.

A size-shrinkable nanoparticle-based combined anti-tumor and anti-inflammatory strategy for enhanced cancer therapy.

Cancer-related inflammation can promote tumorigenesis, tumor growth and tumor metastasis in many types of cancers. Therefore, inhibiting cancer-related inflammation significantly improves cancer therapy. It has been reported that metformin (MET) inhibits the nuclear translocation of nuclear factor-κB (NF-κB), a key factor in cancer-related inflammation.

Dual Receptor Targeting Cell Penetrating Peptide Modified Liposome for Glioma and Breast Cancer Postoperative Recurrence Therapy.

Purpose: Cell penetrating peptides (CPPs) were widely used as motifs for drug delivery to tumor. In former study, an RGD reverse sequence dGR was used to develop active-targeting liposome R8dGR-Lip, which showed well penetrating ability and treatment efficiency on glioma model. However, recurrence after tumor resection caused by post-operative residual cancer cells was a huge obstacle in tumor treatment.

Tandem Peptide Based on Structural Modification of Poly-Arginine for Enhancing Tumor Targeting Efficiency and Therapeutic Effect.

The nonselectivity of cell penetrating peptides had greatly limited the application in systemic administration. By conjugating a dGR motif to the C-terminal of octa-arginine, the formed tandem peptide R8-dGR had been proved to specifically recognize both integrin αβ and neuropilin-1 receptors. However, the positive charge of poly-arginine would still inevitably lead to rapid clearance in the circulation system.