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Infections caused by Enterobacterales producing New Delhi Metallo‐β‐lactamases (NDMs), Zn(II)‐dependent enzymes hydrolyzing carbapenems, are difficult to treat. Depriving Zn(II) to inactivate NDMs is an effective solution to reverse carbapenems resistance in NDMs‐producing bacteria. However, specific Zn(II) deprivation and better bacterial outer membrane penetrability in vivo are challenges. Herein, authors present a pathogen‐primed liposomal antibiotic booster (M‐MFL@MB), facilitating drugs transportation into bacteria and removing Zn(II) from NDMs. M‐MFL@MB introduces bismuth nanoclusters (BiNCs) as a storage tank of Bi(III) for achieving ROS‐initiated Zn(II) removal. Inspired by bacteria‐specific maltodextrin transport pathway, meropenem‐loaded BiNCs are camouflaged by maltodextrin‐cloaked membrane fusion liposome to cross the bacterial envelope barrier via selectively targeting bacteria and directly outer membrane fusion. This fusion disturbs bacterial membrane homeostasis, then triggers intracellular ROS amplification, which activates Bi(III)‐mediated Zn(II) replacement and meropenem release, realizing more precise and efficient NDMs producer treatment. Benefiting from specific bacteria‐targeting, adequate drugs intracellular accumulation and self‐activation Zn(II) replacement, M‐MFL@MB rescues all mice infected by NDM producer without systemic side effects. Additionally, M‐MFL@MB decreases the bacterial outer membrane vesicles secretion, slowing down NDMs producer's transmission by over 35 times. Taken together, liposomal antibiotic booster as an efficient and safe tool provides new strategy for tackling NDMs producer‐induced infections. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) develops resistance to tyrosine kinase inhibitors (TKIs). Here, we evaluated the efficacy of radiotherapy and continuation of TKIs in patients with advanced NSCLC with oligoprogression after EGFR‐TKIs. Methods: From January 2011 to January 2019, 33 patients with EGFR‐mutated NSCLC on TKIs were treated by radiotherapy and continuation of TKIs for oligoprogressive disease. The primary endpoints were median progression‐free survival 1 (mPFS1), mPFS2, and median overall survival (mOS). PFS1 was measured from the start of EGFR‐TKIs therapy to the oligoprogression of the disease. PFS2 was measured from the date of oligoprogression to the further progression of the disease, while OS was calculated from oligoprogression to death from any cause or was censored at the last follow‐up date. Result: The mPFS1, mPFS2, and mOS were 11.0 (95% CI, 4.4–17.6), 6.5 (95% CI, 1.4–11.6) and 21.8 (95% CI, 14.8–28.8) months, respectively. Univariate analysis showed that EGFR mutation type (p = 0.024), radiotherapy method (p = 0.001), and performance status (p = 0.017) were significantly correlated with PFS2. Univariate analysis showed that sex (p = 0.038), smoking history (p = 0.031), EGFR mutation type (p = 0.012), and radiotherapy method (p = 0.009) were significantly correlated with OS. Multivariate analysis suggested that radiotherapy method (p = 0.001) and performance status (p = 0.048) were prognostic factors for PFS2, and radiotherapy method (p = 0.040) was a prognostic factor for OS. Conclusion: Radiotherapy with continued TKIs is effective for EGFR‐mutated NSCLC with oligoprogression, and it should be conducted as soon as possible. T790M+ patients have higher sensitivity to radiotherapy, and patients with good performance status and stereotactic body radiation therapy have better PFS2 and OS. Almost all EGFR mutation‐positive advanced NSCLC patients treated with TKI will progress. The definition of oligometastasis disease included ≤5 metastases with ≤3 organs involved, and all metastatic sites could be amenable to local radical treatment. Radiotherapy with continued TKIs is effective for EGFR‐mutated NSCLC with oligoprogression. [ABSTRACT FROM AUTHOR]

Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the "Zn2+ interference"‐mediated glycolysis inhibition and Zn2+‐activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. It is discovered that ZIF‐8 (zinc imidazolate metal–organic frameworks) can induce abrupt intracellular Zn2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through "Zn2+ interference"‐triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn2+‐activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up‐regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes are loaded in ZIF‐8 concurrently tethered by hyaluronic acid (HA), constructing a "nanoenabled energy interrupter ". Such a rational design presents a preferential accumulation tendency to tumor sites due to the active CD44‐targeting mechanisms, specifically achieves remarkable systematic energy exhaustion in melanoma cells, and affords 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verifies a fascinating therapeutic platform enabling ion interference‐inductive starvation strategy for effective tumor therapy. [ABSTRACT FROM AUTHOR]

B Tumor Starvation Therapy b In article number 2103534 by Zhenzhong Zhang, Junjie Liu, Jinjin Shi, and co-workers, a "nano-enabled energy interrupter"-initiated novel paradigm of tumor starvation therapy is proposed. Nano-enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion (Adv. Sci. 7/2022) The energy interrupter shows a preferential tumor systemic energy exhaustion without obvious side effects by synergizing the "Zn SP 2+ sp interference"-mediated glycolysis inhibition and Zn SP 2+ sp -activating GLUT1 (glucose transporter 1) tumor specific depletion. [Extracted from the article]

Liver fibrosis is a progressive histological manifestation that happens in almost all chronic liver diseases. An unabated liver fibrosis may eventually develop into liver cirrhosis or hepatocellular carcinoma. Yet, the strategy for reversal of liver fibrosis is still limited. Herein, a biomimetic nano‐regulator (P‐ZIF8‐cirDNAzyme) is developed to affect both collagen synthesis and degradation in liver to remodel collagen microenvironment. It is found that Zn (II) interference can efficiently inhibit collagen synthesis in activated hepatic stellate cells (aHSC) by inactivating proline 4 hydroxylase and affecting many fibrosis‐related signaling pathways. Meanwhile, Zn (II)‐dependent circular DNAzymes (cirDNAzymes) are used to efficiently silence tissue inhibitors of metalloproteinase‐1, accelerating the degradation of collagen. They act in concert to recover the balance between collagen deposition and degradation. Additionally, ZIF‐8‐cirDNAzyme is coated by platelet membrane (PM) for precisely targeting aHSC via PM's inflammatory tropism and CD62p–CD44 interaction. In carbon tetrachloride‐induced fibrotic mice, P‐ZIF‐8‐cirDNAzyme shows a potent anti‐fibrotic effect, greatly reducing the expression of collagen by 73.12% and restoring liver function nearly to normal. This work proposes a prospective platform enabling ion interference and gene silencing, collectively acting in aHSC for reversal of liver fibrosis. [ABSTRACT FROM AUTHOR]

The clinical outcomes of programmed cell death protein‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) blockade are usually limited by the multiple immune evasion mechanism of the tumor, as well as the immune storm caused by "off‐target" effects of the PD‐1/PD‐L1 antibody. Here, a previously unknown strategy is proposed to synergize the "Ca2+ interference" mediated M2‐like tumor‐associated macrophages (TAM) re‐education and Ca2+‐activating locally PD‐L1 depletion for immunotherapy. The authors discover that calcium‐containing nanoparticles can induce significant "Ca2+ interference" effect and simultaneously reset TAM toward the M1 phenotype through activation of multiple inflammation‐related signaling pathways, as well as NLRP3 inflammasomes, and promoting in situ tumor‐associated antigen release. In addition, a circular aptamer‐DNAzyme conjugate (cAD) is designed with a tumor‐targeting ability and its catalytic shear activity can be specifically activated by Ca2+, which reduces potential autoimmune‐like disorders of PD‐L1 antibody. By simply integrating the ultra‐high pH‐sensitive calcium peroxide nanoparticles with cAD into one nanosystem, it is demonstrated that the nanosystem not only arrest primary tumor progression and lung metastasis but also provides a long‐term immunological memory, which can protect against tumor rechallenge. Therefore, this work provides an attractive strategy for boosting tumor immunotherapy. [ABSTRACT FROM AUTHOR]