Digitonin-Loaded Nanoscale Metal-Organic Framework for Mitochondria-Targeted Radiotherapy-Radiodynamic Therapy and Disulfidptosis.

The efficacy of radiotherapy (RT) is limited by inefficient X-ray absorption and reactive oxygen species generation, upregulation of immunosuppressive factors, and a reducing tumor microenvironment (TME). Here, the design of a mitochondria-targeted and digitonin (Dig)-loaded nanoscale metal-organic framework, Th-Ir-DBB/Dig, is reported to overcome these limitations and elicit strong antitumor effects upon low-dose X-ray irradiation. Built from ThO(OH) secondary building units (SBUs) and photosensitizing Ir(DBB)(ppy) (Ir-DBB, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; ppy = 2-phenylpyridine) ligands, Th-Ir-DBB exhibits strong RT-radiodynamic therapy (RDT) effects via potent radiosensitization with high-Z SBUs for hydroxyl radical generation and efficient excitation of Ir-DBB ligands for singlet oxygen production.

STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics.

Nanoscale Metal-Organic Layer Reprograms Cellular Metabolism to Enhance Photodynamic Therapy and Antitumor Immunity.

Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3-bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production.

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy.

Nanoscale coordination polymer synergizes photodynamic therapy and toll-like receptor activation for enhanced antigen presentation and antitumor immunity.

While activating antitumor immunity with toll-like receptor (TLR) agonists provides a promising approach toward cancer immunotherapy, existing TLR agonists, including resiquimod (R848), have shown poor tumor selectivity and ineffective TLR activation in tumors for optimal antitumor effects. We hypothesized that improved delivery of TLR agonists to tumors and their effective combination with tumor antigens could significantly enhance their antitumor efficacy. Here, we report a novel nanoscale coordination polymer, Ce6/R848, for the co-delivery of Ce6 photosensitizer to elicit immunogenic cell death via photodynamic therapy (PDT) and cholesterol-conjugated R848 (Chol-R848) for tumor-selective TLR7/8 activation.

Co-delivery of three synergistic chemotherapeutics in a core-shell nanoscale coordination polymer for the treatment of pancreatic cancer.

The combination chemotherapy regimen FOLFIRINOX comprising folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin is the first-line treatment for patients with advanced pancreatic cancer, but its use remains prohibitive for the majority of patients due to severe side effects. Here, we report a core-shell nanoscale coordination polymer (NCP) nanoparticle co-delivering a potent and synergistic combination of oxaliplatin, gemcitabine, and SN38 (OGS), for the treatment of pancreatic cancer in mouse models. OGS contains key synergistic components of FOLFIRINOX in a controllable drug ratio.