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Hypoxia is characteristic of the tumor microenvironment, which is correlated with resistance to photodynamic therapy (PDT), radiotherapy, chemotherapy, and immunotherapy. Catalase is potentially useful to catalyze the conversion of endogenous H 2 O 2 to O 2 for hypoxia reversion. However, the efficient delivery of catalase into the hypoxia regions of tumors is a huge challenge. Here, we report the self-assembly of ultra-acid-sensitive polymer conjugates of catalase and albumin into nanomicelles that are responsive to the acidic tumor microenvironment. The immunogenicity of catalase is mitigated by the presence of albumin, which reduces the cross-linking of catalase with B cell receptors, resulting in improved pharmacokinetics. The ultra acid sensitivity of the nanomicelles makes it possible to efficiently escape the lysosomal degradation after endocytosis and permeate into the interior of tumors to reverse hypoxia in vitro and in vivo. In mice bearing triple-negative breast cancer, the nanomicelles loaded with a photosensitizer effectively accumulate and penetrate into the whole tumors to generate a sufficient amount of O 2 to reverse hypoxia, leading to enhanced efficacy of PDT without detectable side effects. These findings provide a general strategy of self-assembly to design low-immunogenic ultra-acid-sensitive comicelles of protein-polymer conjugates to reverse tumor hypoxia, which sensitizes tumors to PDT.

Chemotherapy remains as the first-choice treatment option for triple-negative breast cancer (TNBC). However, the limited tumor penetration and low cellular internalization efficiency of current nanocarrier-based systems impede the access of anticancer drugs to TNBC with dense stroma and thereby greatly restricts clinical therapeutic efficacy, especially for TNBC bone metastasis. In this work, biomimetic head/hollow tail nanorobots were designed through a site-selective superassembly strategy. We show that nanorobots enable efficient remodeling of the dense tumor stromal microenvironments (TSM) for deep tumor penetration. Furthermore, the self-movement ability and spiky head markedly promote interfacial cellular uptake efficacy, transvascular extravasation, and intratumoral penetration. These nanorobots, which integrate deep tumor penetration, active cellular internalization, near-infrared (NIR) light-responsive release, and photothermal therapy capacities into a single nanodevice efficiently suppress tumor growth in a bone metastasis female mouse model of TNBC and also demonstrate potent antitumor efficacy in three different subcutaneous tumor models., (© 2023. The Author(s).)

Meticulous surface patterning of nanoparticles with anisotropic patches as analogs of functional groups offers fascinating potential in many fields, particularly in controllable materials assembly. However, patchy colloids generally evolve into high-symmetry solid structures, mainly because the assembly interactions arise between patches via patch-to-patch recognition. Here, we report an assembly concept, that is, a soft patch, which enables selective and directional fusion of liquid droplets for producing highly asymmetrical hollow nanospacecrafts. Our approach enables precise control of hollow nanoparticle diameters by manipulating droplet fusion regions. By controlling the patch number, more orientations are accessible to droplet fusion, allowing for increased degrees of complexity of hollow self-assemblies. The versatility and curvature-selective growth of this strategy are demonstrated on three nonspherical nanoparticles, enabling the creation of highly asymmetric nanospacecrafts. By patterning Au-core Ag-shell nanorods, the nanospacecraft can be programmed in response to either H 2 O 2 or near-infrared light, exhibiting dual-mode response behavior with a 208% increase in the diffusion coefficient in both modes compared with other nanoscale low-asymmetry active materials. Overall, these findings are a significant step toward designing new patch interactions for materials self-assembly for creating complex hollow colloids and functional nanodevices that are otherwise inaccessible.

The synergetic photodynamic/photothermal therapy, activated via a single-second near-infrared (NIR-II) laser and guided by photoacoustic imaging (PAI), receives significant attention for precise in vivo therapy. However, due to the lack of a corresponding theranostic agent, it faces a great challenge for practical clinical implementation. Here, we present a single diagnostic and therapeutic nanoplatform named carbon nitride nanoparticles (CN-NPs) for efficient NIR-II PAI-guided photodynamic therapy (PDT)/photothermal therapy (PTT). The CN-NPs were obtained by incorporating an aromatic compound (PTCDA) with a large π-structure into melem by high-temperature polymerization. The absorption of the obtained CN-NPs was significantly enhanced compared with pristine melem. Under 1064 nm laser illumination, sufficient reactive oxygen species (ROS) generated by CN-NPs could reduce the mitochondrial membrane potential. Moreover, the CN-NPs exhibited an efficient PTT effect through improved photothermal stability and high photo-to-heat conversion efficiency (47.6%). We were also able to monitor the accumulation and metabolism of CN-NPs in vivo of mice in real time using PAI. The in vivo experiments proved that the CN-NPs could inhibit tumor growth and recurrence completely under 1064 nm. Thus, the proposed innovative strategy would open a new avenue to explore and construct NIR-II responsive nanoplatforms with enhanced performance and safety for multimodal phototheranostics.

Oxygen consumption but hypoxic tumor environment has been considered as the major obstacle in photodynamic therapy. Although oxygen-supplied strategies have been reported extensively, they still suffer from the complicated system and unsatisfied PDT efficiency. Herein, one-component layered nickel silicate nanoplatforms (LNS NPs) are successfully synthesized using natural vermiculite as the silica source, which can simultaneously supply oxygen (O 2 ) and generate superoxide radicals (O 2 -• ) under near-infrared irradiation. The appropriate electron band structure endows LNS NPs with attractive optical properties, where the bandgap edges determine the performance of redox activity and spectral response characteristic. Evidenced by both in vitro and in vivo investigations, LNS NPs can generate sufficient superoxide radicals under 660 nm laser irradiation to induce tumor cell apoptosis even in a severe hypoxic environment, which benefits from self-supplied oxygen. Besides, the photoacoustic oxy-hem imaging and histologic assay further demonstrated that the generated oxygen can relieve the inherent intratumoral hypoxia. Therefore, LNS NPs not only serve as superoxide radical generator but also produce oxygen to modulate hypoxia, suggesting that it can be used for superoxide radical-mediated photodynamic therapy with enhanced antitumor effect.

Single component agent-based near-infrared phototheranostics has captivated researchers in cancer treatment over recent decades. However, the current single-component agents rarely alleviate the hypoxic microenvironment in tumor cells, which severely limits the development of photodynamic therapy. Here, we report a new phototheranostic agent, single-component black graphite carbon nitride nanoparticles (named CN-B NPs), synthesized through thermal copolymerization. Compared with unmodified graphitic carbon nitride (g-C3N4), the absorption of CN-B NPs in the near-infrared region was enhanced. Through in vitro and in vivo studies, we demonstrated that CN-B NPs can be used as a near-infrared phototheranostic agent in both normoxia and hypoxia, simultaneously allowing infrared thermal/photoacoustic imaging and photodynamic/photothermal co-therapy, thereby resulting in remarkable inhibition of tumor growth. This approach could provide a new method to achieve multimodal phototheranostics using a single-component material.

The elaboration of nanotechnology offers valuable therapeutic options to overcome the blood-brain barrier and enable the treatment of brain diseases. However, to date, limit work has been done to reveal the fate of nanoparticles within the brain, which largely hinders their safe and effective applications. Here we demonstrated that the commonly-used organic nanoparticles reconstituted high density lipoprotein and poly(ethylene glycol)-b-poly(lactic acid) nanoparticles were cleared relatively fast from the brain (half-life <5 h). Notably, through various transgenic mice and pharmacological inhibition approaches, we revealed that the paravascular glymphatic pathway plays a key role (about 80%) in the brain clearance of the nanoparticles, and disclosed that microglia-mediated transportation is essential for facilitating nanoparticles elimination through the paravascular route. In addition, we witnessed a significant decline in the brain clearance of both of the nanoparticles in Alzheimer's model mice where the glymphatic system is impaired. These findings provide insightful data on the fate of nanoparticles in the brain, which would shed new light into the rational design and safe application of nanoparticles for brain drug delivery., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020. Published by Elsevier B.V.)

Nanoparticles have been widely used in biomedical research as drug carriers or imaging agents for living animals. Blood circulation is crucial for the delivery of nanoparticles, which enter the bloodstream through injection, inhalation, or dermal exposure. However, the clearance kinetics of nanoparticles in blood circulation has been poorly studied, mainly because of the limitations of conventional detection methods, such as insufficient blood sample volumes or low spatial-temporal resolution. In addition, formation of nanoparticle aggregates is a key determinant for biocompatibility and drug delivery efficiency. Aggregation behavior of nanoparticles in blood is studied using dynamic light scattering in serum or serum protein solutions, which is still very different from in vivo condition. In this work, we monitored the dynamics of nanoparticle concentration and formation of nanoparticle aggregates in the bloodstream in live animals using in vivo flow cytometry (IVFC). The results indicated that nanoparticles in smaller size could stay longer in the bloodstream. Polyethylene glycol (PEG)-modification could prolong circulating time and reduce the formation of aggregates in the blood circulation. Our work shows that IVFC can be a powerful tool for pharmacokinetic studies of nanoparticles and other drug carriers, assessing cell-targeting efficiency, as well as potentially measuring cardiac output and hepatic function in vivo., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The dissemination, seeding, and colonization of circulating tumor cells (CTCs) serve as the root of distant metastasis. As a key step in the early stage of metastasis formation, colonization of CTCs in the (pre-)metastatic niche appears to be a valuable target. Evidence showed that inflammatory neutrophils possess both a CTC- and niche-targeting property by the intrinsic cell adhesion molecules on neutrophils. Inspired by this mechanism, we developed a nanosize neutrophil-mimicking drug delivery system (NM-NP) by coating neutrophils membranes on the surface of poly(latic-co-glycolic acid) nanoparticles (NPs). The membrane-associated protein cocktails on neutrophils membrane were mostly translocated to the surface of NM-NP via a nondisruptive approach, and the biobinding activity of neutrophils was highly preserved. Compared with uncoated NP, NM-NP exhibited enhanced cellular association in 4T1 cell models under shear flow in vitro, much higher CTC-capture efficiency in vivo, and improved homing to the premetastatic niche. Following loading with carfilzomib, a second generation of proteasome inhibitor, the NM-NP-based nanoformulation (NM-NP-CFZ) selectively depleted CTCs in the blood, prevented early metastasis and potentially inhibited the progress of already-formed metastasis. Our NP design can neutralize CTCs in the circulation and inhibit the formation of a metastatic niche.

Surgical resection is a mainstay of brain tumor treatments. However, the completed excision of malignant brain tumor is challenged by its infiltrative nature. Contrast enhanced magnetic resonance imaging is widely used for defining brain tumor in clinic. However its ability in tumor visualization is hindered by the transient circulation lifetime, nontargeting specificity, and poor blood brain barrier (BBB) permeability of the commercially available MR contrast agents. In this work, we developed a two-order targeted nanoprobe in which MR/optical imaging reporters, tumor vasculature targeted cyclic [RGDyK] peptides, and BBB-permeable Angiopep-2 peptides are labeled on the PAMAM-G5 dendrimer. This nanoprobe is supposed to first target the α(V)β(3) integrin on tumor vasculatures. Increased local concentration of nanoprobe facilitates the association between BBB-permeable peptides and the low-density lipoprotein receptor-related protein (LRP) receptors on the vascular endothelial cells, which further accelerates BBB transverse of the nanoprobe via LRP receptor-mediated endocytosis. The nanoprobes that have penetrated the BBB secondly target the brain tumor because both α(V)β(3) integrin and LRP receptor are highly expressed on the tumor cells. In vivo imaging studies demonstrated that this nanoprobe not only efficiently crossed intact BBB in normal mice, but also precisely delineated the boundary of the orthotropic U87MG human glioblastoma xenograft with high target to background signal ratio. Overall, this two-order targeted nanoprobe holds the promise to noninvasively visualize brain tumors with uncompromised BBB and provides the possibility for real-time optical-image-guided brain tumor resection during surgery., (© 2011 American Chemical Society)

Photodynamic therapy (PDT) takes advantage of photosensitizers (PSs) to generate reactive oxygen species (ROS) for cell killing when excited by light. It has been widely used in clinic for therapy of multiple cancers. Currently, all the FDA-approved PSs, including porphyrin, are all small organic molecules, suffering from aggregation-caused quenching (ACQ) issues in biological environment and lacking tumor targeting capability. Nanoparticles (NPs) with size between 20 nm and 200 nm possess tumor targeting capability due to the enhanced permeability and retention (EPR) effect. It is urgent to develop a new strategy to form clinical-approved-PSs-based NPs with improved ROS generation capability. In this study, we report a strategy to overwhelm the ACQ of porphyrin by doping it with a type of aggregation-induced emission (AIE) luminogen to produce a binary NPs with high biocompatibility, and enhanced fluorescence and ROS generation capability. Such NPs can be readily synthesized by mixing a porphyrin derivative, Ce6 with a typical AIE luminogen, TPE-Br. Here, our experimental results have demonstrated the feasibility and effectiveness of this strategy, endowing it a great potential in clinical applications. [ABSTRACT FROM AUTHOR]

The fluorescence-based in vivo flow cytometry (IVFC) is an emerging tool to monitor circulating cells in vivo. As a noninvasive and real-time diagnostic technology, the fluorescence-based IVFC allows long-term monitoring of circulating cells without changing their native biological environment. It has been applied for various biological applications (e.g., monitoring circulating tumor cells). In this work, we will review our recent works on fluorescence-based IVFC. The operation principle and typical biological applications will be introduced. In addition, the recent advances in IVFC flow cytometry based on photoacoustic effects and other label-free detection methods such as imaging-based methods, diffuse-light methods, hybrid multimodality methods and multispectral methods are also summarized. [ABSTRACT FROM AUTHOR]