The clinical translation of tumor hypoxia intervention modalities still falls short of expectation, restricted by poor biocompatibility of oxygen-carrying materials, unsatisfactory oxygen loading performance, and abnormally high cellular oxygen consumption-caused insufficient hypoxia relief. Herein, a carrier-free oxygen nano-tank based on modular fluorination prodrug design and co-assembly nanotechnology is elaborately exploited, which is facilely fabricated through the molecular nanoassembly of a fluorinated prodrug (FSSP) of pyropheophorbide a (PPa) and an oxygen consumption inhibitor (atovaquone, ATO). The nano-tank adeptly achieves sufficient oxygen enrichment while simultaneously suppressing oxygen consumption within tumors for complete tumor hypoxia alleviation. Significant, the fluorination module in FSSP not only confers favorable co-assemblage of FSSP and ATO, but also empowers the nanoassembly to readily carry oxygen. As expected, it displays excellent oxygen carrying capacity, favorable pharmacokinetics, on-demand laser-triggerable ATO release, closed-loop tumor hypoxia relief, and significant enhancement to PPa-mediated PDT in vitro and in vivo. This study provides a novel nanotherapeutic paradigm for tumor hypoxia intervention-enhanced cancer therapy.

Main conventional antithrombotic therapies often suffer from unsatisfactory treatment outcomes and the risk of undesirable tissue hemorrhage. Deep clot penetration, on-demand drug activation, and release within the clots remain significant challenges. While past efforts to develop nanomedicines and prodrugs have improved safety at the expense of therapeutic effects. Herein, we develop a self-piercing and self-activating nanoassembly composed of an oxidation-sensitive prodrug (TGL-S-Fmoc, TSF) of ticagrelor (TGL) and IR808 (a photothermal/photodynamic dual-effect photosensitizer). TSF readily coassembles with IR808 into a carrier-free hybrid nanomedicine. Upon laser irradiation, IR808 enables photothermal thrombolysis and deep clot penetration of TSF while also synergistically facilitating prodrug activation triggered by IR808-generated singlet oxygen (1O2) and the endogenous hydrogen peroxide within the clots. Following fibrin-targeting modification, the nanoassembly achieves self-indicating thrombus-targeted accumulation, self-piercing deep clot penetration, dual-priming prodrug activation, and inside-out thrombus ablation with favorable safety in vivo. This study advances the clinical translation of antithrombotic prodrugs and nanomedicines.

Abstract Background: Cancer stem cells (CSCs) are recognized as the culprits of chemoresistance, tumor metastasis and relapse. Conventional chemotherapeutic drugs not only fail to effectively kill CSCs, but induce the acquisition of stemness characteristics in non-stem cancer cells. Meanwhile, most anti-CSCs drugs display marginal inhibitory effects on cancer cell proliferation. Therefore, developing a cancer cells/CSCs double-killing modality is highly desired. Methods: A carrier-free nano-cocktail is developed through precise co-assembly of a redox-responsive dimeric prodrug of docetaxel (DTX) and salinomycin (SAL, an anti-CSCs drug) for breast cancer treatment. In this study, we systematically investigated the co-assembly mechanism, reduction-responsive drug release behavior, cellular uptake efficiency, synergistic cytotoxicity, and anti-CSCs efficacy of the nano-cocktail through in vitro experiments. Additionally, the pharmacokinetics, biodistribution and synergistic anti-tumor/CSCs activity were explored in vivo. Results: Precision combination of DTX and SAL not only shows synergistic tumor killing activity, but also sharply reduces the proportion of CSCs in tumors. More importantly, tumor-specific prodrug activation-initiated drug release confers high drug co-delivery efficiency and low off-target toxicity risk to the nano-cocktail. As expected, such a one-stone-two-birds nanomedicine has excellent performance on tumor stemness depletion, antitumor responses, and treatment safety in a breast cancer mouse xenograft model. Conclusion: This study advances cancer cells/CSCs double-killing nanotherapeutics towards clinical breast cancer therapy.

Clinical thrombus therapy continues to be challenged by unsatisfactory antithrombotic outcomes and high bleeding risk. Rational design of prodrugs for thrombolytic agents is expected to ameliorate this situation. Nevertheless, a significant obstacle is the inadequate penetration of prodrugs and prodrug-engineered nanomedicines, which hampers their effective interaction with the excessive stimuli produced in thrombi, resulting in suboptimal drug activation. Herein, a clot-piercing nanoassembly is reported to facilitate photothermal clot penetration, adaptable drug activation, anti-inflammatory action, and synergetic antithrombotic therapy, the nanoassembly is molecularly co-assembled using a photothermal photosensitizer and a reactive oxygen species (ROS)-sensitive antiplatelet dimeric prodrug. The nanoassembly demonstrates multiple advantages, including facile fabrication, high drug co-loading capacity, long circulation time in the blood, thrombus-targeting accumulation, photothermal-potentiated clot-piercing deep penetration, on-demand prodrug activation in response to high H2O2 concentrations inside the clots, and anti-inflammatory/antiplatelet synergy. These advantages result in significantly enhanced antithrombotic efficacy in vivo with favorable safety. This study presents a new paradigm for the development of prodrug-driven antithrombotic nanomedicines.

Thrombotic cerebro-cardiovascular diseases are the leading causes of disability and death worldwide. However, current drug therapeutics are compromised by narrow therapeutic windows, unsatisfactory thrombolysis effects, severe bleeding events, and high recurrence rates. In this study, we exploit a self-propelling nano-penetrator with high fuel loading and controllable motion features, which is molecularly co-assembled using a photothermal photosensitizer (DiR) and a photothermal-activable NO donor (BNN6). The precisely engineered nano-penetrator of the BNN6-DiR fuel pair shows distinct advantages in terms of NO productivity and autonomous motion under laser irradiation. In animal models of artery/vein thrombosis and acute ischemic stroke, the self-fueled nano-penetrator enables self-navigated thrombus-homing accumulation, self-propelled clot deep penetration, fluorescence image-guided photothermal/mechanical thrombolysis, and NO-mediated prevention of thrombosis recurrence and acute ischemic stroke salvage. As expected, the molecularly self-fueled nano-penetrator displayed favorable therapeutic outcomes without bleeding risk compared to the clinically available thrombolytic drug. This study offers a facile, safe, and effective nonpharmaceutical modality towards the clinical treatment of thrombosis and ischemic stroke.

Bioorthogonal chemistry has emerged as a promising approach for anticancer applications, enabling targeted tumor detection, imaging, and therapeutic interventions. Particularly, the ingenious encounter of bioorthogonal chemistry and biomedical nanotechnology has opened up new avenues for precise diagnosis and treatment of malignant tumors. Given the remarkable advancements in bioorthogonal chemistry-driven anticancer nanotherapeutics, it is imperative to review the latest breakthroughs. Herein, we aim to outline the emerging trends in the fields at the intersection of bioorthogonal chemistry and biomedical nanotechnology for precision cancer theranostics, with special attention on bioorthogonal chemistry-driven tumor-targeting modalities, nanoprobes, and nanomedicines. This review underscores the rationale, advantages, and challenges of integrating bioorthogonal chemistry with biomedical nanotechnology and tumor biology to develop desirable anticancer nanotherapeutics.

Nitric oxide (NO) is a gaseous molecule endowed with diverse biological functions, offering vast potential in the realm of cancer treatment. Considerable efforts have been dedicated to NO-based cancer therapy owing to its good biosafety and high antitumor activity, as well as its efficient synergistic therapy with other antitumor modalities. However, delivering this gaseous molecule effectively into tumor tissues poses a significant challenge. To this end, nano drug delivery systems (nano-DDSs) have emerged as promising platforms for in vivo efficient NO delivery, with remarkable achievements in recent years. This review aims to provide a summary of the emerging NO-driven antitumor nanotherapeutics. Firstly, the antitumor mechanism and related clinical trials of NO therapy are detailed. Secondly, the latest research developments in the stimulation of endogenous NO synthesis are presented, including the regulation of nitric oxide synthases (NOS) and activation of endogenous NO precursors. Moreover, the emerging nanotherapeutics that rely on tumor-specific delivery of NO donors are outlined. Additionally, NO-driven combined nanotherapeutics for multimodal cancer theranostics are discussed. Finally, the future directions, application prospects, and challenges of NO-driven nanotherapeutics in clinical translation are highlighted.

The source data include Figure 2c-d, g-h,j-l, Figure 3c-d,f-g,i-k, Figure 4c,f,h, Figure 5c-d, f, i, Figure 6c-d, h, Figure 7c-d,f, h, Supplementary Fig 4, 5b, 6, 7, 8, 9, 10, 12, 13b, 15, 16, 20, 23, 24, and 25.

Photodynamic therapy (PDT) has been extensively investigated as a spatiotemporally noninvasive and controllable modality for cancer treatment. However, the intracellular antioxidant systems mainly consisting of thioredoxin (Trx) and glutathione (GSH) significantly counteract and prevent reactive oxygen species (ROS) accumulation, resulting in a serious loss of PDT efficiency. To address this challenge, we propose that PDT can be improved by precisely blocking antioxidant systems. After molecular engineering and synergistic cytotoxic optimization, a DSPE-PEG2K-modified dual-drug nanoassembly (PPa@GA/DSPE-PEG2K NPs) of pyropheophorbide a (PPa) and gambogic acid (GA) is successfully constructed. Interestingly, GA can effectively destroy intracellular antioxidant systems by simultaneously inhibiting Trx and GSH. Under laser irradiation, the cell-killing effects of PPa is significantly enhanced by GA-induced inhibition of the antioxidant systems. As expected, PPa@GA/DSPE-PEG2K nanoparticles demonstrate potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Such a carrier-free self-sensitized nanotherapeutic offers a novel co-delivery strategy for effective PDT.

随着生物纳米技术在药物递送领域的深入研究和广泛应用,研究人员设计和构建多种功能各异的纳米药物递送系统用于抗肿瘤药物的高效递送.其中,将前药策略与纳米递药技术进行有机整合的前药纳米组装体已经逐渐成为纳米药物递送系统中一个非常重要的领域.前药设计的关键在于药物分子结构的合理修饰和前药在靶部位的选择性高效激活.近年来,研究发现肿瘤微环境智能响应型前药纳米组装体能够在靶部位选择性快速释药,其已成为癌症诊疗相关研究的重要平台.首先,对肿瘤氧化还原微环境和常用的氧化还原敏感化学桥连进行介绍;其次,分别介绍肿瘤氧化还原微环境智能响应型聚合物大分子前药纳米组装体和小分子前药纳米组装体;最后,对前药纳米组装体优缺点和整个纳米药物递送系统的临床转化前景进行总结和分析.通过对以上内容进行综述,以期为肿瘤微环境智能响应型前药纳米系统的设计与构建提供参考.

Thrombotic cardio-cerebrovascular diseases seriously threaten human health. Currently, conventional thrombolytic treatments are challenged by the low utilization, inferior thrombus penetration, and high off-target bleeding risks of most thrombolytic drugs, resulting in unsatisfactory treatment outcomes. Herein, it is proposed that these challenges can be overcome by precisely integrating the conventional thrombolytic strategy with photothermal therapy. After co-assembly engineering optimization, a fibrin-targeting peptide-decorated nanoassembly of DiR (a photothermal probe) and ticagrelor (TGL, an antiplatelet drug) is prepared for thrombus-homing delivery, abbreviated as FT-DT NPs. The elaborately engineered nanoassembly shows multiple advantages, including simple preparation with high drug co-loading capacity, synchronous delivery of two drugs with long systemic circulation, thrombus-targeted accumulation with self-indicating function, as well as photothermal-potentiated thrombus penetration and thrombolysis with high therapeutic efficacy. As expected, FT-DT NPs not only show bright fluorescence signals in the embolized vessels, but also perform photothermal/antiplatelet synergistic thrombolysis in vivo. This study offers a simple and versatile co-delivery nanoplatform for imaging-guided photothermal/antiplatelet dual-modality thrombolysis.