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Intracellular bacterial (ICB) infection is one of the most life‐threatening cases of drug resistance, and photodynamic therapy (PDT) is challenged by limited light penetration into tissues and unspecific toxicity to host cells. Herein, theranostic nanoparticles (NPs) are developed to facilitate on‐demand activation of photosensitizers inside ICBs and persistent PDT of deep‐tissue ICB infections. Mechanoluminescent SrAl2O4:Eu2+ and persistence luminescent CaS:Eu2+ are sequentially deposited on mesoporous silica to prepare mSC, followed by encapsulation by bacterial membranes with loaded nitroreductase (NTR)‐activatable methylene blue (nMB) to obtain mSC‐nMB@BM NPs. The fluorescence quenching of nMB with mSC offers few cytotoxicities even under ultrasonication, and bacterial membrane coatings mediate the specific NP internalization into ICB‐infected macrophages. Bacterial pore‐forming toxins trigger nMB release from NPs, and intrabacterial NTR rejuvenates methylene blue probes from nMB for real‐time imaging of ICB infections. Ultrasonication of NPs continuously excites the rejuvenated methylene blue to generate reactive oxidative species and reduce viable ICBs by 3.54 log magnitude folds. NP treatment on ICB‐infected mice exhibits full survival and restores viscera functions without any pathological abnormality. Therefore, this concise NP design demonstrates capabilities of bacterial membrane‐mediated specific internalization, bacterial toxin‐triggered release and intrabacterial NTR‐rejuvenation of fluorescent probes, and persistent internal light‐illumination for ICB theranostics. [ABSTRACT FROM AUTHOR]

Thrombus therapy is challenged by potential bleeding risk of thrombolytic agents, and external irradiation is usually needed in thrombus imaging. Herein, highly efficient theranostic platforms are designed for piezoelectric‐Fenton‐photodynamic thrombolysis and endogenous thrombus imaging in response to the elevated shear stress at the thrombus site. Piezoelectric tetragonal barium titanate (tBT) nanoparticles (NPs) are coated with Fe3+‐coordinated metal‐organic frameworks (MOFs), followed by inoculation of chlorin e6‐luminol conjugates and heparin absorption to obtain theranostic tBT@MOFCL/Hep NPs. Shear stress‐induced piezopotential on NPs accelerates Fe3+/Fe2+ transformation to deplete MOF layers, activates Fenton reaction and produces reactive oxidative species (ROS) for non‐pharmacological thrombolysis. In the meantime, the site‐specific ROS generation oxidizes luminol and the chemiluminescent resonance energy transfer with chlorin e6 generates red fluorescence for thrombus imaging without using external light irradiation. After intravenous injection into a carotid artery thrombosis model, the heparin‐mediated thrombus targeting yields 6.5‐fold higher luminescent intensity at the thrombus site. Thrombi in the carotid arteries are almost completely dissolved with integration of piezoelectric dynamic therapy, piezopotential‐enhanced Fenton reaction, and chemiluminescence‐excited photodynamic therapy, while causing no haematologic and histopathologic abnormality. This study demonstrates a concise strategy to generate shear stress‐responsive built‐in piezoelectric potentials, site‐specific non‐pharmacological thrombolysis, self‐illuminating, and stenosis degree‐adaptable thrombus imaging. [ABSTRACT FROM AUTHOR]

Effective thrombolysis is critical to rapidly rebuild blood flow for thrombosis patients. Drug delivery systems have been developed to address inadequate pharmacokinetics of thrombolytic agents, but challenges still remain in the timely removal of blood clots regarding the dense fibrin networks. Herein, rod-shaped tubular micromotors were developed to achieve efficient penetration and thorough destruction of thrombi. By using electrospun fiber fragments as the template, urokinase (uPA)-loaded polydopamine (PDA) microtubes with surface decorated fucoidan (FuPDA uPA) were prepared at the aspect ratio of around 2. One E. coli Nissle 1917 (EcN) was assembled into one microtube to construct a FuPDA uPA @EcN hybrid micromotor through PDA adhesion and L-aspartate induction. The pharmacokinetic analysis indicates that the encapsulation of uPA into micromotors extends the half-life from 0.4 to 5.6 h and increases the bioavailability over 10 times. EcN-propelled motion elevates adsorption capacities of FuPDA uPA @EcN for more than four times compared with that of FuPDA uPA. The fucoidan-mediated targeting causes 2-fold higher thrombolysis capacity in vitro and over 10-fold higher uPA accumulation in thrombi in vivo. In the treatment of venous thrombi at mouse hindlimbs, intravenous administration of FuPDA uPA @EcN completely removed blood clots with almost full recovery of blood flows and apparently alleviated tail bleeding. It should be noted that FuPDA uPA @EcN treatment at a reduced uPA dose caused no significant difference in the blood flow rate compared with those of FuPDA uPA. The synergistic action of fucoidan-induced targeting and EcN-driven motion provides a prerequisite for promoting thrombolytic efficacy and reducing uPA dose and bleeding side effect. The standard treatment to thrombosis patient is intravenous infusion of thrombolytic agents, but the associated bleeding complications and impairment of normal haemostasis greatly offset the therapeutic benefits. Drug delivery systems have been developed to address the limitations of inadequate pharmacokinetics of thrombolytic agents, but challenges still exist in less efficient penetration into dense networks for thorough destruction of thrombi. Up to now only few attempts have been made to construct nano-/micromotors for combating thrombosis and there is no single case that antithrombosis is assisted by bacteria or cells-propelled motors. Herein, bacteria-propelled microtubes were developed to carry urokinase for efficient penetration into blood clots and effective thrombolysis. The synergistic action of bacteria-driven motion and specific ligand-induced targeting holds a promising treatment strategy for life-threatening cardiovascular diseases such as thrombosis and atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]

The shapes of drug carriers have significant effects on the drug's blood circulation lifetime and tumor accumulation levels. In this study, nonspherical drug carriers of fiber rods are enhanced with hierarchically targeting capabilities to achieve long circulation in blood, on-demand recovery of cell targeting ligands in tumor tissues and dual ligands-mediated cellular uptake. Zwitterionic polymers are conjugated on fiber rods via acid-labile linkers as stealth coronas to reduce the capture by macrophages and shield the targeting ligands. Compared with commonly used poly(ethylene glycol), the zwitterionic grafts show significantly higher inhibition of protein adsorption and lower internalization by macrophages, leading to around 2 folds longer blood circulation and over 2.5 folds higher drug accumulation in tumors than pristine fiber rods. To address the conflicts between blood circulation and cellular uptake, the zwitterionic coronas are efficiently removed in the slightly acidic tumor microenvironment. The exposure of targeting ligands could activate the internalization by tumor cells, resulting in higher cytotoxicity and tumor accumulation than those with stable linkers. Fiber rods are grafted with dual ligands of folate and biotin, and the optimal ligand densities and ratios are determined to maximize the tumor cell uptake. Compared with other treatment, fiber rods with decorated zwitterionic coronas and acid-liable exposure of dual targeting ligands enhance the suppression of tumor growth, prolong animal survival, and cause less lung metastasis. The development of fiber rods with hierarchically targeting capabilities shows great potential in improving the blood circulation, tumor accumulation and cellular uptake, and eventually promoting therapeutic efficacy. The targeted delivery of chemotherapeutic agents will encounter a series of biological and pathological barriers. In this study, fiber rods were empowered with hierarchically targeting capabilities to resolve the conflict between blood circulation and cellular uptake. This strategy has shown several advantages over the existing methods. Firstly, zwitterionic polymers were used as blood circulation ligands, and concrete evidence was provided via head-to-head comparison with commonly used poly(ethylene glycol) ligands in the macrophage uptake and in vivo tissue distribution. Secondly, the depletion of circulation ligands and on-demand exposure of targeting ligands in tumor tissues showed crucial effects on the uptake by tumor cells. Thirdly, the densities and ratios of the dual targeting ligands were initially determined for a maximal cellular internalization. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has evolved as an essential method for infection control, but is confronted with challenges in terms of low oxygen supply, possible toxicity during light irradiation, and nonpersistent action. Herein, to address these limitations, black phosphorus (BP) is used as a photosensitizer and decorated with Pt nanoparticles and aminobenzyl-2-pyridone (APy) moieties to obtain BP@APy-Pt. The stability of BP is improved through the capture and occupation of lone-pair electrons after reductive deposition of Pt nanoparticles and covalent conjugation of APy. Pt nanoparticles on BP@APy-Pt catalyze the decomposition of endogenous H 2 O 2 to produce oxygen for consecutive cycles with a stable production capacity. The light exposure to BP@APy-Pt generates significantly higher 1 O 2 levels than those of BP/light, and the generated 1 O 2 is partially captured by APy moieties. The captured 1 O 2 during 20 min of illumination shows a constant release for 24 h in the dark. The cycled storage and release feature eliminates the toxicity of 1 O 2 at high levels during illumination and leads to efficient destruction of S. aureus and P. aeruginosa. Compared to the healing rates after treatment with BP/light (57.6%), BP@Pt/light (64.8%), BP@APy/light (77.8%), and BP@APy-Pt (48.5%), the skin wounds with infected S. aureus are fully healed after BP@APy-Pt/light treatment. Blood vessels and hair follicles are regenerated to resemble those of normal skin. Thus, this study expands the PDT strategy through integration with oxygen generation, 1 O 2 storage, and persistent release to promote bactericidal efficacy and eliminate side effects.