STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy.

Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor T cells have received clinical approval for monotherapy and combination treatment use in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs) have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here we review the current development of STING-activating therapeutics in both preclinical or clinical stages.

Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection.

Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.

Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors.

Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment (TME). The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic TME, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity.

Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

Nanotechnology-based Strategies for Molecular Imaging, Diagnosis, and Therapy of Organ Transplantation.

Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection.

Ultrasensitive Ionic Conductors with Tunable Resistance Switching Temperature Enabled by Phase Transformation of Polymer Cocrystals.

Phase-transformable ionic conductors (PTICs) show significant prospects for functional applications due to their reversible resistance switching property. However, the representative design principle of PTICs is utilizing the melt-crystallization transition of ionic liquids, and the resistance switching temperatures of such PTICs cannot be tuned as desired. Herein, a new strategy is proposed to design PTICs with on-demand resistance switching temperatures by using the melt-crystallization transition of polymer cocrystal phase, whose melting temperature shows a linear relationship with the polymer compositions. Owing to the melt of polymer cocrystal domains and the tunable migration of ions in the resistance switching region, the obtained PTICs display ultrahigh temperature sensitivity with a superior temperature coefficient of resistance of -8.50% °C-1 around human body temperature, as compared to various ionic conductors previously reported. Therefore, the PTICs can detect tiny temperature variation, allowing for the intelligent applications for overheating warning and heat dissipation. It is believed that this work may inspire future researches on the development of advanced soft electrical devices.

Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS: Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS: Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION: The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING: This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).