pH-Assisted multichannel heat shock monitoring in the endoplasmic reticulum with a pyridinium fluorophore.

Heat shock is a global health concern as it causes permanent damage to living cells and has a relatively high mortality rate. Therefore, diagnostic tools that facilitate a better understanding of heat shock damage and the defense mechanism at the sub-cellular level are of great importance. In this report, we have demonstrated the use of a pyridinium-based fluorescent molecule, PM-ER-OH, as a 'multichannel' imaging probe to monitor the pH change associated with a heat shock in the endoplasmic reticulum. Among the three pyridinium derivatives synthesized, PM-ER-OH was chosen for study due to its excellent biocompatibility, good localization in the endoplasmic reticulum, and intracellular pH response signaled by a yellow fluorescence (λ max = 556 nm) at acidic pH and a far red fluorescence (λ max = 660 nm) at basic pH. By changing the excitation wavelength, we could modulate the fluorescence signal in 'turn-ON', single excitation ratiometric and 'turn-OFF' modes, making the fluorophore a 'multichannel' probe for both ex vitro and in vitro pH monitoring in the endoplasmic reticulum. The probe could efficiently monitor the pH change when heat shock was applied to cells either directly or in a pre-heated manner, which gives insight on cellular acidification caused by heat stress.

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development.

Nanoformulation of active payloads or pharmaceutical ingredients (APIs) has always been an area of interest to achieve targeted, sustained, and efficacious delivery. Various delivery platforms have been explored, but loading and delivery of APIs have been challenging because of the chemical and structural properties of these molecules. Polymersomes made from amphiphilic block copolymers (ABCPs) have shown enormous promise as a tunable API delivery platform and confer multifold advantages over lipid-based systems. For example, a COVID booster vaccine comprising polymersomes encapsulating spike protein (ACM-001) has recently completed a Phase I clinical trial and provides a case for developing safe drug products based on ABCP delivery platforms. However, several limitations need to be resolved before they can reach their full potential. In this Perspective, we would like to highlight such aspects requiring further development for translating an ABCP-based delivery platform from a proof of concept to a viable commercial product.

Metal-Organic Frameworks Meet Polymers: From Synthesis Strategies to Healthcare Applications.

Metal-organic frameworks (MOFs) have been at the forefront of nanotechnological research for the past decade owing to their high porosity, high surface area, diverse configurations, and controllable chemical structures. They are a rapidly developing class of nanomaterials that are predominantly applied in batteries, supercapacitors, electrocatalysis, photocatalysis, sensors, drug delivery, gas separation, adsorption, and storage. However, the limited functions and unsatisfactory performance of MOFs resulting from their low chemical and mechanical stability hamper further development. Hybridizing MOFs with polymers is an excellent solution to these problems, because polymers-which are soft, flexible, malleable, and processable-can induce unique properties in the hybrids based on those of the two disparate components while retaining their individuality. This review highlights recent advances in the preparation of MOF-polymer nanomaterials. Furthermore, several applications wherein the incorporation of polymers enhances the MOF performance are discussed, such as anticancer therapy, bacterial elimination, imaging, therapeutics, protection from oxidative stress and inflammation, and environmental remediation. Finally, insights from the focus of existing research and design principles for mitigating future challenges are presented.

Albumin-Based Therapeutics Capable of Glutathione Consumption and Hydrogen Peroxide Generation for Synergetic Chemodynamic and Chemotherapy of Cancer.

A nanoscale therapeutic system with good biocompatibility was facilely fabricated by the coassembly of human serum albumin and glucose oxidase (GOD), where the former was pretreated with metal ions through a chelating agent or the chemotherapeutic prodrug oxaliplatin (Oxa(IV)). Among different chelating metal ions used, Mn2+ ion was selected to produce hydroxyl radical (•OH) efficiently through Fenton-like reaction, while GOD loaded in the system was able to generate a large amount of hydrogen peroxide for promoting efficient conversion into highly toxic •OH. In the meanwhile, the conversion of the Oxa(IV) prodrug into chemotherapeutic Oxa(II) was beneficial for the consumption of glutathione, thereby enhancing the chemodynamic therapy (CDT) efficacy. Based on the combined chemotherapy and CDT, the treatment with this system leads to superior antitumor outcome.

Thiolate-Assisted Route for Constructing Chalcogen Quantum Dots with Photoinduced Fluorescence Enhancement.

Despite great efforts in the development of diverse nanomaterials, a general route to synthesize metal-free chalcogen quantum dots (QDs) is still lacking. Moreover, the modification of chalcogen QDs is a bottleneck that severely hinders their applications. Herein, we develop a facile method to construct different chalcogen QDs (including S QDs, Se QDs, and Te QDs) with the assistance of thiolates. In addition to stabilizing chalcogen QDs, the thiolates also endow the chalcogen QDs with favorable modifiability. Different from most dyes whose fluorescence is quenched after short-term light irradiation, the prepared chalcogen QDs have significantly enhanced fluorescence emission under continuous light irradiation. Taking advantage of the distinctive photoinduced fluorescence enhancement property, long-time cell imaging with superb performance is realized using the chalcogen QDs. It is envisioned that the chalcogen QDs show promising potential as fluorescent materials in different fields beyond bioimaging.

Self-assembled semiconducting polymer based hybrid nanoagents for synergistic tumor treatment.

There is an impending need for the development of carrier-free nanosystems for single laser triggered activation of phototherapy, as such approach can overcome the drawbacks associated with irradiation by two distinct laser sources for avoiding prolonged treatment time and complex treatment protocols. Herein, we developed a self-assembled nanosystem (SCP-CS) consisting of a new semiconducting polymer (SCP) and encapsulated ultrasmall CuS (CS) nanoparticles. The SCP component displays remarkable near infrared (NIR) induced photothermal ability, enhanced reactive oxygen species (ROS) generation, and incredible photoacoustic (PA) signals upon activation by 808 nm laser for phototherapy mediated cancer ablation. The CuS component improves the PA imaging ability of SCP-CS, and also enhances photo-induced chemodynamic efficacy. Attributed to promoted single laser-triggered hyperthermia and enhanced ROS generation, the SCP-CS nanosystem shows effective intracellular uptake and intratumoral accumulation, enhanced tumor suppression with reduced treatment time, and devoid of any noticeable toxicity.

Missing-Linker-Assisted Artesunate Delivery by Metal-Organic Frameworks for Synergistic Cancer Treatment.

Clinical translation of artesunate (ATS) as a potent antitumor drug has been obstructed by its rapid degradation and low bioavailability. Herein, we report the development of an ATS nanomedicine through the self-assembly with Mn[Co(CN)6 ]2/3 □1/3 metal-organic frameworks (MOFs) that have hidden missing linkers. The defects in MOFs originating from the missing linkers play a key role in increasing the biological stability and tumor accumulation of ATS. Chlorin e6 (Ce6) and ATS can be co-loaded into MOFs for a synergistic antitumor efficacy. In the presence of intracellular HCO3- , Mn2+ acts as an efficient catalyst to promote the bicarbonate-activated H2 O2 system which oxidizes ATS to generate reactive oxygen species and induce oxidative death to cancer cells. The released [CoIII (CN)6 ] linker undergoes a redox reaction with intracellular glutathione to prevent the scavenging ability of reactive oxygen species, contributing to synergistic chemodynamic therapy of ATS and photodynamic therapy of Ce6. Thus, defect-engineered MOFs with hidden missing linkers hold great promise in advancing the practical use of ATS as an antitumor medicine.

Ultrasmall Alloy Nanozyme for Ultrasound- and Near-Infrared Light-Promoted Tumor Ablation.

The therapeutic effect of chemodynamic therapy (CDT) is significantly restricted by the stern reaction conditions and slow reaction rate of the Fenton reaction (pH 3-4). Herein, we report an ultrasmall trimetallic (Pd, Cu, and Fe) alloy nanozyme (PCF-a NEs) possessing dynamic active-site synergism, thus exhibiting a cascade glutathione peroxidase and peroxidase (POD) mimicking activities in circumneutral pH. PCF-a NEs exhibit photothermally augmented POD property and high photothermal conversion efficiency (62%) for synergistic tumor cell apoptosis. In addition, ultrasound can also enhance the mass transfer at active catalytic sites of PCF-a NEs, in turn accelerating Fenton-like reaction for tumor-specific CDT. This work provides a strategy for engineering alloy nanozymes in a bioinspired way for the amplification of intratumor reactive oxygen species in response to external stimuli, demonstrating enhanced efficiency for the inhibition of tumor growth in vitro and in vivo.

Hybrid Carbon Dot Assembly as a Reactive Oxygen Species Nanogenerator for Ultrasound-Assisted Tumor Ablation.

The efficacy of reactive oxygen species (ROS)-based therapy is substantially constrained by the limited ROS generation, stern activation conditions, and lack of a straightforward reaction paradigm. Carbon dots (CDs) have been highly sought after for therapeutic applications for their biocompatibility and intrinsic fluorescence imaging capabilities, making them suitable for ROS generation. Herein, we synthesized a CD-based ultrasmall hybrid nanostructure possessing active sites of Mo, Cu, and IR-780 dye. After cooperative self-assembly with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol), the obtained assembly (CMIR-CDa) exhibits near-infrared fluorescence imaging and photoacoustic tomography. Interestingly, CMIR-CDa can generate singlet oxygen (1O2), hydroxyl radical (·OH), and superoxide radical anion (O2 • -) upon ultrasound stimulus owing to its sonosensitizing and enzyme-mimicking properties, showing an enhanced efficacy for tumor ablation in vivo. The collective in vitro and in vivo results indicate that CMIR-CDa has a high potency as an ROS nanogenerator under US irradiation, even at a low concentration. The present study offers an approach for engineering hybrid CDs in a bioinspired way for intratumoral ROS augmentation in response to deep tissue penetrable external stimuli.

Morphology-dependent resonance enhanced nonlinear photoacoustic effect in nanoparticle suspension: a temporal-spatial model.

The morphology-dependent resonances (MDRs) hotspot, ubiquity formed between the pairs of nanoparticles in close vicinity, has garnered considerable recent attention. By extending this phenomenon to pulse-laser irradiated nanoparticle suspension, we demonstrate that such collective optical/thermal enhancement can give rise to the nonlinear photoacoustic (PA) generation. In this study, a temporal-spatial analytical expression is derived to quantitatively describe the nonlinear PA signal generation from nanoparticles, incorporating the Grüneisen increase at the microscopic individual particle level and MRDs enhancement at the macroscopic suspension level. The dependence of PA nonlinearity on the critical contributors, including the laser pulse width, the particle size, and the statistical interparticle spacing, is quantitatively discussed. The theory is well validated with the finite element method (FEM) and experimentally proved with semiconducting polymer nanoparticles (SPN) suspension. This work may pave a new direction towards effective MDR based nonlinear PA contract agent design.

Clearable Black Phosphorus Nanoconjugate for Targeted Cancer Phototheranostics.

Therapeutic efficacy of synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) is limited by complex conjugation chemistry, absorption wavelength mismatch, and inadequate biodegradability of the PDT-PTT agents. Herein, we designed biocompatible copper sulfide nanodot anchored folic acid-modified black phosphorus nanosheets (BP-CuS-FA) to overcome these limitations, consequently enhancing the therapeutic efficiency of PDT-PTT. In vitro and in vivo assays reveal good biocompatibility and commendable tumor inhibition efficacy of the BP-CuS-FA nanoconjugate because of the synergistic PTT-PDT mediated by near-infrared laser irradiation. Importantly, folic acid unit could target folate receptor overexpressed cancer cells, leading to enhanced cellular uptake of BP-CuS-FA. BP-CuS-FA also exhibits significant contrast effect for photoacoustic imaging, permitting its in vivo tracking. The photodegradable character of BP-CuS-FA is associated with better renal clearance after the antitumor therapy in vivo. The present research may facilitate further development on straightforward approaches for targeted and imaging-guided synergistic PDT-PTT of cancer.

Structural Engineering of Luminogens with High Emission Efficiency Both in Solution and in the Solid State.

Developing molecules with high emission efficiency both in solution and the solid state is still a great challenge, since most organic luminogens are either aggregation-caused quenching or aggregation-induced emission molecules. This dilemma was overcome by integrating planar and distorted structures with long alkyl side chains to achieve DAπAD type emitters. A linear diphenyl-diacetylene core and the charge transfer effect ensure considerable planarity of these molecules in the excited state, allowing strong emission in dilute solution (quantum yield up to 98.2 %). On the other hand, intermolecular interactions of two distorted cyanostilbene units restrict molecular vibration and rotation, and long alkyl chains reduce the quenching effect of the π-π stacking to the excimer, eventually leading to strong emission in the solid state (quantum yield up to 60.7 %).

A Hypoxia-Responsive Albumin-Based Nanosystem for Deep Tumor Penetration and Excellent Therapeutic Efficacy.

Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia-responsive human serum albumin (HSA)-based nanosystem (HCHOA) is reported, prepared by cross-linking the hypoxia-sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)-conjugated HSA (HC) and oxaliplatin prodrug-conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100-150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic-responsive nanosystem to enhance the tumor penetration and therapeutic effect.

Degradability and Clearance of Inorganic Nanoparticles for Biomedical Applications.

Inorganic nanoparticles with tunable and diverse properties hold tremendous potential in the field of nanomedicine, while having non-negligible toxicity concerns in healthy tissues/organs that have resulted in their restricted clinical translation to date. In the past decade, the emergence of biodegradable or clearable inorganic nanoparticles has made it possible to completely solve this long-standing conundrum. A comprehensive understanding of the design of these inorganic nanoparticles with their metabolic performance in the body is of crucial importance to advance clinical trials and expand their biological applications in disease diagnosis. Here, a diverse variety of biodegradable or clearable inorganic nanoparticles regarding considerations of the size, morphology, surface chemistry, and doping strategy are highlighted. Their pharmacokinetics, pathways of metabolism in the body, and time required for excretion are discussed. Some inorganic materials intrinsically responsive to various conditions in the tumor microenvironment are also introduced. Finally, an overview of the encountered challenges is provided along with an outlook for applying these inorganic nanoparticles toward future clinical translations.