Nanomedicines loaded in macrophages (MAs) can actively target tumors without dominantly relying on the enhanced permeability and retention (EPR) effect, making them effective for treating EPR-deficient malignancies. Herein, copper-crosslinked carbon dot clusters (CDCs) are synthesized with both photodynamic and chemodynamic functions to manipulate MAs, aiming to direct the MA-mediated tumor targeting. First, green fluorescent CDs (g-CDs) are prepared by a one-step hydrothermal method. Subsequently, the g-CDs are complexed with divalent copper ions to form copper-crosslinked CDCs (g-CDCs/Cu), which are incubated with MAs for their manipulation. Experimental results revealed that the prepared g-CDCs/Cu displayed good aqueous dispersibility and fluorescent emission properties. The nanoassemblies can be activated to deplete the overexpressed glutathione (GSH) and generate reactive oxygen species (ROS) in the presence of laser irradiation through the combined Cu-mediated chemodynamic therapy and CD-mediated photodynamic therapy. Furthermore, the ROS produced in MAs enabled polarization of MAs to antitumor M1 phenotype, suggesting the future potential use to reverse the immunosuppressive tumor microenvironment. These results obtained from the current study suggest a significant potential to develop g-CDCs/Cu for GSH depletion, ROS generation, and MA M1 polarization as a theransotic agent to tackle cancer.

Nanomaterials with photoresponsivity have garnered attention due to their fluorescence imaging, photodynamic, and photothermal therapeutic properties. In this study, a photoresponsivity nanoassembly was developed by using photosensitizers and carbon dots (CDs). Due to their multiple excitation peaks and multicolor fluorescence emission, especially their membrane-permeating properties, these nanoassemblies can label cells with multiple colors and track cell imaging in real time. Additionally, the incorporation of photosensitizers and CDs provides the nanoassemblies with the potential for photodynamic therapy (PDT) and photothermal therapy (PTT). The nanoassemblies effectively suppressed the activity of Escherichia coli and Staphylococcus aureus through PDT and PTT. Moreover, the nanoassemblies exhibited a high affinity for E. coli and S. aureus. These distinct features confer broad-spectrum antibacterial properties to the nanoassemblies. As a photoresponsivity nanoplatform, these nanoassemblies have demonstrated potential applications in the fields of bioimaging and antimicrobial.

Atherosclerosis, a chronic and progressive condition characterized by the accumulation of inflammatory cells and lipids within artery walls, remains a leading cause of cardiovascular diseases globally. Despite considerable advancements in drug therapeutic strategies aimed at managing atherosclerosis, more effective treatment options for atherosclerosis are still warranted. In this pursuit, the emergence of β-cyclodextrin (β-CD) as a promising therapeutic agent offers a novel therapeutic approach to drug delivery targeting atherosclerosis. The hydrophobic cavity of β-CD facilitates its role as a carrier, enabling the encapsulation and delivery of various therapeutic compounds to affected sites within the vasculature. Notably, β-CD-based nanoassemblies possess the ability to reduce cholesterol levels, mitigate inflammation, solubilize hydrophobic drugs and deliver drugs to affected tissues, making these nanocomponents promising candidates for atherosclerosis management. This review focuses on three major classes of β-CD-based nanoassemblies, including β-CD derivatives-based, β-CD/polymer conjugates-based and polymer β-CD-based nanoassemblies, highlighting a variety of formulations and assembly methods to improve drug delivery and therapeutic efficacy. These β-CD-based nanoassemblies exhibit a variety of therapeutic mechanisms for atherosclerosis and offer systematic strategies for overcoming barriers to drug delivery. Finally, we discuss the present obstacles and potential opportunities in the development and application of β-CD-based nanoassemblies as novel therapeutics for managing atherosclerosis and addressing cardiovascular diseases.

One of the key aspects of coping efficiently with complex pathological conditions is delivering the desired therapeutic compounds with precision in both space and time. Therefore, the focus on nuclear-targeted delivery systems has emerged as a promising strategy with high potential, particularly in gene therapy and cancer treatment. Here, we explore the design of supramolecular nanoassemblies as vehicles to deliver specific compounds to the nucleus, with the special focus on polymer and peptide-based carriers that expose nuclear localization signals. Such nanoassemblies aim at maximizing the concentration of genetic and therapeutic agents within the nucleus, thereby optimizing treatment outcomes while minimizing off-target effects. A complex scenario of conditions, including cellular uptake, endosomal escape, and nuclear translocation, requires fine tuning of the nanocarriers\' properties. First, we introduce the principles of nuclear import and the role of nuclear pore complexes that reveal strategies for targeting nanosystems to the nucleus. Then, we provide an overview of cargoes that rely on nuclear localization for optimal activity as their integrity and accumulation are crucial parameters to consider when designing a suitable delivery system. Considering that they are in their early stages of research, we present various cargo-loaded peptide- and polymer nanoassemblies that promote nuclear targeting, emphasizing their potential to enhance therapeutic response. Finally, we briefly discuss further advancements for more precise and effective nuclear delivery.

On-surface synthesis is a powerful method that has emerged recently to fabricate a large variety of atomically precise nanomaterials on surfaces based on polymerization. It is very successful for thermally activated reactions within the framework of heterogeneous catalysis. As a result, it often lacks selectivity. We propose to use selective activation of specific bonds as a crucial ingredient to synthesize desired molecules with high selectivity. In this approach, thermally nonaccessible products are expected to arise in photolytically activated on-surface reactions with high selectivity. We demonstrate for assembled 2,2\'-dibromo biphenyl clusters on Cu(111) that the thermal and photolytic activations yield distinctly different products, combining submolecular resolution of individual product molecules in real-space imaging by scanning tunneling microscopy with chemical identification in X-ray photoelectron spectroscopy and supported by ab initio calculations. The photolytically activated Ullmann coupling of 2,2\'-dibromo biphenyl is highly selective, with only one identified product. It starkly contrasts the thermal reaction, which yields various products because alternate pathways are activated at the reaction temperature. Our study extends on-surface synthesis to a directed formation of thermally inaccessible products by direct bond activation. It promises tailored reactions of nanomaterials within the framework of on-surface synthesis based on the photolytic activation of specific bonds.

Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery.

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules\' sensitivity. The extension of the carbon chains improved the prodrugs\' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Stimuli-responsive nano-assemblies from amphiphilic macromolecules could undergo controlled structural transformations and generate diverse macroscopic phenomenon under stimuli. Due to the controllable responsiveness, they have been applied for broad material and biomedical applications, such as biologics delivery, sensing, imaging, and catalysis. Understanding the mechanisms of the assembly-disassembly processes and structural determinants behind the responsive properties is fundamentally important for designing the next generation of nano-assemblies with programmable responsiveness. In this review, we focus on structural determinants of assemblies from amphiphilic macromolecules and their macromolecular level alterations under stimuli, such as the disruption of hydrophilic-lipophilic balance (HLB), depolymerization, decrosslinking, and changes of molecular packing in assemblies, which eventually lead to a series of macroscopic phenomenon for practical purposes. Applications of stimuli-responsive nano-assemblies in delivery, sensing and imaging were also summarized based on their structural features. We expect this review could provide readers an overview of the structural considerations in the design and applications of nanoassemblies and incentivize more explorations in stimuli-responsive soft matters.

The global antibiotic resistance crisis has drawn attention to the development of treatment methods less prone to inducing drug resistance, such as antimicrobial photodynamic therapy (aPDT). However, there is an increasing demand for new photosensitizers capable of efficiently absorbing in the near-infrared (NIR) region, enabling antibacterial treatment in deeper sites. Additionally, advanced strategies need to be developed to avert drug resistance stemming from prolonged exposure. Herein, we have designed a conjugated oligoelectrolyte, namely TTQAd, with a donor-acceptor-donor (D-A-D) backbone, enabling the generation of reactive oxygen species (ROS) under NIR light irradiation, and cationic adamantaneammonium groups on the side chains, enabling the host-guest interaction with curcubit[7]uril (CB7). Due to the amphiphilic nature of TTQAd, it could spontaneously form nanoassemblies in aqueous solution. Upon CB7 treatment, the positive charge of the cationic adamantaneammonium group was largely shielded by CB7, leading to a further aggregation of the nanoassemblies and a reduced antibacterial efficacy of TTQAd. Subsequent treatment with competitor guests enables the release of TTQAd and restores its antibacterial effect. The reversible supramolecular switch for regulating the antibacterial effect offers the potential for the controlled release of active photosensitizers, thereby showing promise in preventing the emergence of drug-resistant bacteria.

UNASSIGNED: Most current anti-cancer therapies are associated with major side effects due to a lack of tumor specificity. Appropriate vectorization of drugs using engineered nanovectors is known to increase local concentration of therapeutic molecules in tumors while minimizing their side effects. Mesothelin (MSLN) is a well-known tumor associated antigen overexpressed in many malignancies, in particular in malignant pleural mesothelioma (MPM), and various MSLN-targeting anticancer therapies are currently evaluated in preclinical and clinical assays. In this study, we described, for the first time, the functionalization of fluorescent organic nanoassemblies (NA) with a nanobody (Nb) targeting MSLN for the specific targeting of MSLN expressing MPM cancer cells.
UNASSIGNED: Cell lines from different cancer origin expressing or not MSLN were used. An Nb directed against MSLN was coupled to fluorescent NA using click chemistry. A panel of endocytosis inhibitors was used to study targeted NA internalization by cells. Cancer cells were grown in 2D or 3D and under a flow to evaluate the specificity of the targeted NA. Binding and internalization of the targeted NA were studied using flow cytometry, confocal microscopy and transmission electron microscopy.
UNASSIGNED: We show that the targeted NA specifically bind to MSLN-expressing tumor cells. Moreover, such functionalized NA appear to be internalized more rapidly and in significantly larger proportions compared to naked ones in MSLN+ MPM cells, thereby demonstrating both the functionality and interest of the active targeting strategy. We demonstrated that targeted NA are mainly internalized through a clathrin-independent/dynamin-dependent endocytosis pathway and are directed to lysosomes for degradation. A 3D cell culture model based on MSLN-expressing multicellular tumor spheroids reveals NA penetration in the first superficial layers.
UNASSIGNED: Altogether, these results open the path to novel anticancer strategies based on MSLN-activated internalization of NA incorporating drugs to promote specific accumulation of active treatments in tumors.