No abstract

Immunotherapy aiming to harness the exquisite power of the immune system has emerged as a crucial part of clinical cancer management. However, only a subset of cancer patients responds to current immunotherapy because of low immunogenicity of the tumor cells and immunosuppressive tumor microenvironment. Herein, host–guest prodrug nanovectors are reported for active tumor targeting and combating immune tolerance in tumors. The prodrug nanovectors are designed by integrating hyaluronic acid (HA) and reduction‐labile heterodimer of Pheophorbide A (PPa) and NLG919 into the supramolecular nanocomplexes, where PPa and NLG919 act as a photosensitizer and potent inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO‐1), respectively. Meanwhile, HA is employed to achieve active tumor targeting by recognizing CD44 overexpressed on the surface of tumor cell membranes. Near infrared (NIR) laser irradiation triggers the release of reactive oxygen species to provoke antitumor immunogenicity and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Meanwhile, the immunosuppressive tumor microenvironment (ITM) is reversed by NLG919‐mediated IDO‐1 inhibition. Combination of photodynamic immunotherapy and IDO‐1 blockade efficiently eradicates CT26 colorectal tumors in the immunocompetent mice. The host–guest nanoplatform capable of eliciting effective antitumor immunity by inactivating inhibitory immune response can be applied to other immune modulators for improved cancer immunotherapy.

Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off‐target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ‐binding affinity, stimuli‐responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near‐infrared (NIR)‐absorbing conjugated polymer PDPP3T‐O14 serves as a photothermal core while thermal‐responsive polymer 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine at the outer layer as the NIR‐stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5‐mer β‐sheet breaker peptides LPFFD (Leu‐Pro‐Phe‐Phe‐Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol‐lipid shell for active Aβ‐targeting. The resultant NPs exhibit good Aβ‐targeting ability and obvious photothermal dissociation effect together with Aβ aggregation‐dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti‐amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ‐induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.

In emergency departments, the most common cause of death associated with suspected infected patients is sepsis. In this study, deep learning algorithms were used to predict the mortality of suspected infected patients in a hospital emergency department. During January 2007 and December 2013, 42,220 patients considered in this study were admitted to the emergency department due to suspected infection. In the present study, a deep learning structure for mortality prediction of septic patients was developed and compared with several machine learning methods as well as two sepsis screening tools: the systemic inflammatory response syndrome (SIRS) and quick sepsis-related organ failure assessment (qSOFA). The mortality predictions were explored for septic patients who died within 72 h and 28 days. Results demonstrated that the accuracy rate of deep learning methods, especially Convolutional Neural Network plus SoftMax (87.01% in 72 h and 81.59% in 28 d), exceeds that of the other machine learning methods, SIRS, and qSOFA. We expect that deep learning can effectively assist medical staff in early identification of critical patients.

Second near‐infrared (NIR‐II) fluorescence imaging with deep tissue‐penetration ability holds remarkable potential for cancer diagnosis. However, clinical translation of NIR‐II fluorescence imaging‐based cancer treatment is severely restricted by the low signal‐to‐background ratio due to insufficient tumor specificity of fluorophores. In this study, it is hypothesized that methylglyoxal (MGO), an intermediate metabolite of tumor glycolysis could be used as a potent biomarker for triggering NIR‐II fluorescence imaging‐guided cancer theranostic. For proof‐of‐concept, first a MGO‐activatable NIR‐II fluorescence probe is developed, and then MGO‐responsive “dual lock‐and‐key” nanotheranostics by integrating the NIR‐II fluorophore and a photodynamic prodrug (i.e., hexyl 5‐aminolevulinic acid hydrochloride (HAL)) into one nanoparticle is engineered. The nanotheranostic can be specifically activated with tumorous MGO for NIR‐II fluorescence imaging‐guided combinatory cancer therapy. Upon 808 nm laser irradiation, the activated NIR‐II fluorophore can generate tunable photothermal effect to trigger HAL release. Subsequently, HAL is converted to protoporphyrin IX inside the tumor cells for 655 nm laser irradiation‐induced photodynamic therapy. It is demonstrated that the NIR‐II fluorescence nanotheranostics is highly specifically activated in the tumor and efficiently suppressed 4T1 breast tumor growth in mouse model. The NIR‐II fluorescence imaging‐based nanotheranostic might imply novel insight into reactive metabolite‐activatable precise therapy of tumor.

Tumor metastasis is considered a major cause of cancer‐related human mortalities. However, it still remains a formidable challenge in clinics. Herein, a bioinspired multivalent nanoplatform for the highly effective treatment of the metastatic melanoma is reported. The versatile nanoplatform is designed by integrating indocyanine green and a chemotherapeutic drug (7‐ethyl‐10‐hydroxycamptothecin) into phenylboronic acid (PBA)‐functionalized peptide nanotubes (termed as I/S‐PPNTs). I/S‐PPNTs precisely target tumor cells through multivalent interaction between PBA and overexpressed sialic acid on the tumor surface in order to achieve imaging‐guided combination therapy. It is demonstrated that I/S‐PPNTs are efficiently internalized by the B16‐F10 melanoma cells in vitro in a PBA grafting density–dependent manner. It is further shown that I/S‐PPNTs specifically accumulate and deeply penetrate into both the subcutaneous and lung metastatic B16‐F10 melanoma tumors. More importantly, I/S‐PPNT‐mediated combination chemo‐ and photodynamic therapy efficiently eradicates tumor and suppresses the lung metastasis of B16‐F10 melanoma in an immunocompetent C57BL/6 mouse model. The results highlight the promising potential of the multivalent peptide nanotubes for active tumor targeting and imaging‐guided cancer therapy.

Among these therapies, cancer vaccines represent a promising approach to elicit a protective immune response for long-term tumor regression and metastasis prevention. [2] However, insufficient stimulation of the innate immune system in antigenpresenting cells (APCs) largely limit cancer vaccine-induced antigen cross-presentation and subsequent T-cell immunity activation. [3] Notably, agonists of the innate immune signaling, including Toll-like receptors (TLRs), retinoic acid-inducible gene I-like (RIG-I) receptors, and stimulator of interferon genes (STING), are being exploited as immune adjuvants to improve cancer vaccination efficiency. [4] Activation of STING signaling is particularly promising because it triggers a multifaceted type I interferon (IFN-I) response that stimulates APCs activation and promotes antigen cross-presentation for priming CD8 + cytotoxic T lymphocyte (CTL) response. [5] In addition, activation of STING signaling in other cells also play important roles in cancer immunotherapy. For instance, STING activation in T cell promoted the maintenance of stem celllike CD8 + T cell and enhance CD8 + T cell trafficking and infiltration into solid tumors. [6] STING activation in natural killer (NK) cells could promote NK cell activation, enhance its cytotoxicity and antitumor effect to mediate the clearance of CD8 + T cell-resistant tumors. [7] Recent studies The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8 + cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.

A near-infrared fluorescent probe for MGO imaging in Alzheimer's disease mouse brains was developed.