Virus-like structures for combination antigen protein mRNA vaccination.

Improved vaccination requires better delivery of antigens and activation of the natural immune response. Here we report a lipid nanoparticle system with the capacity to carry antigens, including mRNA and proteins, which is formed into a virus-like structure by surface decoration with spike proteins, demonstrating application against SARS-CoV-2 variants. The strategy uses S1 protein from Omicron BA.1 on the surface to deliver mRNA of S1 protein from XBB.1. The virus-like particle enables specific augmentation of mRNAs expressed in human respiratory epithelial cells and macrophages via the interaction the surface S1 protein with ACE2 or DC-SIGN receptors. Activation of macrophages and dendritic cells is demonstrated by the same receptor binding. The combination of protein and mRNA increases the antibody response in BALB/c mice compared with mRNA and protein vaccines alone. Our exploration of the mechanism of this robust immunity suggests it might involve cross-presentation to diverse subsets of dendritic cells ranging from activated innate immune signals to adaptive immune signals.

A synergistic strategy based on active hydroxymethyl amine compounds and fucoidan for bioprosthetic heart valves with enhancing anti-coagulation and anti-calcification properties.

With an aging population, the patients with valvular heart disease (VHD) are growing worldwide, and valve replacement is a primary choice for these patients with severe valvular disease. Among them, bioprosthetic heart valves (BHVs), especially BHVs trough transcatheter aortic valve replacement, are widely accepted by patients on account of their good hemodynamics and biocompatibility. Commercial BHVs in clinic are prepared by glutaraldehyde cross-linked pericardial tissue with the risk of calcification and thrombotic complications. In the present study, a strategy combines improved hemocompatibility and anti-calcification properties for BHVs has been developed based on a novel non-glutaraldehyde BHV crosslinker hexakis(hydroxymethyl)melamine (HMM) and the anticoagulant fucoidan. Besides the similar mechanical properties and enhanced component stability compared to glutaraldehyde crosslinked PP (G-PP), the fucoidan modified HMM-crosslinked PPs (HMM-Fu-PPs) also exhibit significantly enhanced anticoagulation performance with a 72 % decrease in thrombus weight compared with G-PP in ex-vivo shunt assay, along with the superior biocompatibility, satisfactory anti-calcification properties confirmed by subcutaneous implantation. Owing to good comprehensive performance of these HMM-Fu-PPs, this simple and feasible strategy may offer a great potential for BHV fabrication in the future, and open a new avenue to explore more N-hydroxymethyl compound based crosslinker with excellent performance in the field of biomaterials.

A versatile drug-controlled release polymer brush hybrid non-glutaraldehyde bioprosthetic heart valves with enhanced anti-inflammatory, anticoagulant and anti-calcification properties, and superior mechanical performance.

Transcatheter heart valve replacement (THVR) is a novel treatment modality for severe heart valves diseases and has become the main method for the treatment of heart valve diseases in recent years. However, the lifespan of the commercial glutaraldehyde cross-linked bioprosthetic heart valves (BHVs) used in THVR can only serve for 10-15 years, and the essential reason for the failure of the valve leaflet material is due to these problems such as calcification, coagulation, and inflammation caused by glutaraldehyde cross-linking. Herein, a kind of novel non-glutaraldehyde cross-linking agent bromo-bicyclic-oxazolidine (OX-Br) has been designed and synthesized with both crosslinking ability and in-situ atom transfer radical polymerization (ATRP) function. Then OX-Br treated porcine pericardium (OX-Br-PP) are stepwise modified with co-polymer brushes of reactive oxygen species (ROS) response anti-inflammatory drug conjugated block and anti-adhesion polyzwitterion polymer block through the in-situ ATRP reaction to obtain the functional BHV material MPQ@OX-PP. Along with the great mechanical properties and anti-enzymatic degradation ability similar to glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good biocompatibility, improved anti-inflammatory effect, robust anti-coagulant ability and superior anti-calcification property have been verified for MPQ@OX-PP by a series of in vitro and in vivo investigations, indicating the excellent application potential as a multifunctional heart valve cross-linking agent for OX-Br. Meanwhile, the strategy of synergistic effect with in situ generations of reactive oxygen species-responsive anti-inflammatory drug blocks and anti-adhesion polymer brushes can effectively meet the requirement of multifaceted performance of bioprosthetic heart valves and provide a valuable reference for other blood contacting materials and functional implantable materials with great comprehensive performance.

A chlorogenic acid functional strategy of anti-inflammation, anti-coagulation and promoted endothelial proliferation for bioprosthetic artificial heart valves.

Heart valve replacement has become an optimal choice for the treatment of severe heart valve disease. At present, most commercial bioprosthetic heart valves (BHVs) are made from porcine pericardium or bovine pericardium treated with glutaraldehyde. Nevertheless, due to the toxicity of residual aldehyde groups left after glutaraldehyde cross-linking, these commercial BHVs exhibit poor biocompatibility, calcification, risk of coagulation and endothelialization difficulty, which greatly affects the durability of the BHVs and shortens their service life. In this work, based on a chlorogenic acid functional anti-inflammation, anti-coagulation and endothelialization strategy and dual-functional non-glutaraldehyde cross-linking reagent OX-CO, a kind of functional BHV material OX-CA-PP has been developed from OX-CO cross-linked porcine pericardium (OX-CO-PP) followed by the convenient modification of chlorogenic acid through a reactive oxygen species (ROS) sensitive borate ester bond. The functionalization of chlorogenic acid can reduce the risk of valve leaf thrombosis and promote endothelial cell proliferation, which is beneficial to the formation of a long-term interface with good blood compatibility. Meanwhile, such a ROS responsive behavior can trigger intelligent release of chlorogenic acid on-demand to achieve the inhibition of acute inflammation at the early stage of implantation. The in vivo and in vitro experimental results show that the functional BHV material OX-CA-PP exhibits superior anti-inflammation, improved anti-coagulation, minimal calcification and promoted proliferation of endothelial cells, showing that this non-glutaraldehyde functional strategy has great potential for the application of BHVs and providing a promising reference for other implanted biomaterials.

Duplex Responsive Nanoplatform with Cascade Targeting for Atherosclerosis Photoacoustic Diagnosis and Multichannel Combination Therapy.

The culprits of atherosclerosis are endothelial damage, local disorders of lipid metabolism, and progressive inflammation. Early atherosclerosis is typically difficult to diagnose in time due to the lack of obvious symptoms, thus missing the best period of treatment. In this work, a π-conjugated polymer (PMeTPP-MBT) based on 3,6-bis(4-methylthiophen-2-yl)-2,5-bis(2-octyldodecyl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione is designed as a novel photoacoustic contrast agent. On this basis, an intelligent responsive theranostic nanoplatform (PA/ASePSD) combining astaxanthin and SS-31 peptide and loading with PMeTPP-MBT is developed. The high affinity between the dextran shell with the broken endothelial surface VCAM-1 and CD44 confers active targeting of PA/ASePSD to atherosclerotic lesions. High levels of ROS in the acidic plaque microenvironment act as an intelligent cascade switch to achieve controlled release of astaxanthin, SS-31 peptide, and PMeTPP-MBT for non-invasive photoacoustic diagnosis, as well as plaque inhibition mediated by anti-inflammation and multichannel regulation (including ABCA1, ABCG1, CD36, and LOX-1) of lipid metabolism. Both in vitro and in vivo evaluations confirm the impressive anti-atherosclerotic capability and the accurate photoacoustic diagnosis of PA/ASePSD nanoparticles, thus promising a candidate for early-stage atherosclerosis theranostics.

A versatile modification strategy for functional non-glutaraldehyde cross-linked bioprosthetic heart valves with enhanced anticoagulant, anticalcification and endothelialization properties.

Valvular heart disease is a major threat to human health and transcatheter heart valve replacement (THVR) has emerged as the primary treatment option for severe heart valve disease. Bioprosthetic heart valves (BHVs) with superior hemodynamic performance and compressibility have become the first choice for THVR, and more BHVs have been requested for clinical use in recent years. However, several drawbacks remain for the commercial BHVs cross-linked by glutaraldehyde, including calcification, thrombin, poor biocompatibility and difficulty in endothelialization, which would further reduce the BHVs' lifetime. This study developed a dual-functional non-glutaraldehyde crosslinking reagent OX-VI, which can provide BHV materials with reactive double bonds (CC) for further bio-function modification in addition to the crosslinking function. BHV material PBAF@OX-PP was developed from OX-VI treated porcine pericardium (PP) after the polymerization with 4-vinylbenzene boronic acid and the subsequent modification of poly (vinyl alcohol) and fucoidan. Based on the functional anti-coagulation and endothelialization strategy and dual-functional crosslinking reagent, PBAF@OX-PP has better anti-coagulation and anti-calcification properties, higher biocompatibility, and improved endothelial cells proliferation when compared to Glut-treated PP, as well as the satisfactory mechanical properties and enhanced resistance effect to enzymatic degradation, making it a promising candidate in the clinical application of BHVs. STATEMENT OF SIGNIFICANCE: Transcatheter heart valve replacement (THVR) has become the main solution for severe valvular heart disease. However, bioprosthetic heart valves (BHVs) used in THVR exhibit fatal drawbacks such as calcification, thrombin and difficulty for endothelialization, which are due to the glutaraldehyde crosslinking, resulting in a limited lifetime to 10-15 years. A new non-glutaraldehyde cross-linker OX-VI has been designed, which can not only show great crosslinking ability but also offer the BHVs with reactive double bonds (CC) for further bio-function modification. Based on the dual-functional crosslinking reagent OX-VI, a versatile modification strategy was developed and the BHV material (PBAF@OX-PP) has been developed and shows significantly enhanced anticoagulant, anti-calcification and endothelialization properties, making it a promising candidate in the clinical application of BHVs.

A universal strategy for the construction of polymer brush hybrid non-glutaraldehyde heart valves with robust anti-biological contamination performance and improved endothelialization potential.

With the intensification of the aging population and the development of transcatheter heart valve replacement technology (THVR), clinical demand for bioprosthetic valves is increasing rapidly. However, commercial bioprosthetic heart valves (BHVs), mainly manufactured from glutaraldehyde cross-linked porcine or bovine pericardium, generally undergo degeneration within 10-15 years due to calcification, thrombosis and poor biocompatibility, which are closely related to glutaraldehyde cross-linking. In addition, endocarditis caused by post-implantation bacterial infection also accelerates the failure of BHVs. Herein, a functional cross-linking agent bromo bicyclic-oxazolidine (OX-Br) has been designed and synthesized to crosslink BHVs and construct a bio-functionalization scaffold for subsequent in-situ atom transfer radical polymerization (ATRP). The porcine pericardium cross-linked by OX-Br (OX-PP) exhibits better biocompatibility and anti-calcification property than the glutaraldehyde-treated porcine pericardium (Glut-PP) as well as comparable physical and structural stability to Glut-PP. Furthermore, the resistance to biological contamination especially bacterial infection of OX-PP along with anti-thrombus and endothelialization need to be enhanced to reduce the risk of implantation failure due to infection. Therefore, amphiphilic polymer brush is grafted to OX-PP through in-situ ATRP polymerization to prepare polymer brush hybrid BHV material SA@OX-PP. SA@OX-PP has been demonstrated to significantly resist biological contamination including plasma proteins, bacteria, platelets, thrombus and calcium, and facilitate the proliferation of endothelial cells, resulting in reduced risk of thrombosis, calcification and endocarditis. Altogether, the proposed crosslinking and functionalization strategy synergistically achieves the improvement of stability, endothelialization potential, anti-calcification and anti-biofouling performances for BHVs, which would resist the degeneration and prolong the lifespan of BHVs. The facile and practical strategy has great potential for clinical application in fabricating functional polymer hybrid BHVs or other tissue-based cardiac biomaterials. STATEMENT OF SIGNIFICANCE: Bioprosthetic heart valves (BHVs) are widely used in valve replacements for severe heart valve disease, and clinical demand is increasing year over year. Unfortunately, the commercial BHVs, mainly cross-linked by glutaraldehyde, can serve for only 10-15 years because of calcification, thrombus, biological contamination, and difficulties in endothelialization. Many studies have been conducted to explore non-glutaraldehyde crosslinkers, but few can meet high requirements in all aspects. A new crosslinker, OX-Br, has been developed for BHVs. It can not only crosslink BHVs but also serve as a reactive site for in-situ ATRP polymerization and construct a bio-functionalization platform for subsequent modification. The proposed crosslinking and functionalization strategy synergistically achieves the high requirements for stability, biocompability, endothelialization, anti-calcification, and anti-biofouling propeties of BHVs.

Targeting Theranostics of Atherosclerosis by Dual-Responsive Nanoplatform via Photoacoustic Imaging and Three-In-One Integrated Lipid Management.

Atherosclerosis, as a life-threatening cardiovascular disease with chronic inflammation and abnormal lipid enrichment, is often difficult to treat timely due to the lack of obvious symptoms. In this work, a theranostic nanoplatform is constructed for the noninvasive in vivo diagnosis, plaque-formation inhibition, and the lesion reversal of atherosclerosis. A three-in-one therapeutic complex is constructed and packaged along with a polymeric photoacoustic probe into nanoparticles named as PLCDP@PMH, which indicates an atherosclerosis-targeting accumulation and a reactive oxygen species (ROS)/matrix metalloproteinase (MMP) dual-responsive degradation. The photoacoustic probe suggests a lesion-specific imaging on atherosclerotic mice with an accurate and distinct recognition of plaques. At the same time, the three-in-one complex performs an integrated lipid management through the inhibition of macrophages M1-polarization, liver X receptor (LXR)-mediated up-regulation of ATP-binding cassette transporter A1/G1 (ABCA1/G1) and the cyclodextrin-assisted lipid dissolution, which lead to the reduced lipid uptake, enhanced lipid efflux, and actuated lipid removal. The in vivo evaluations reveal that PLCDP@PMH can suppress the lesion progression and further reverse the formed plaques under a diet without high fat. Hence, PLCDP@PMH provides a candidate for the theranostics of early-stage atherosclerosis and delivers an impressive potential on the reversal of formed atherosclerotic lesions.

N-Arylimidazoliums as Highly Selective Biomimetic Antimicrobial Agents.

Antibiotic resistance has become one of the greatest health threats in the world. In this study, a charge-dispersed dimerization strategy is described for the antimicrobial peptide (AMP) mimics via a tunable cationic charge to improve the selectivity between prokaryotic microbes and eukaryotic cells. This strategy is demonstrated with a series of charge-dispersed AMP mimics based on N-arylimidazolium skeletons. These N-arylimidazolium AMP mimics show potent antibacterial activity against strains along with a low rate of drug resistance, good hemocompatibility, and low cytotoxicity. In addition to the elimination of planktonic bacteria, N-arylimidazolium AMP mimics can also inhibit biofilm formation and destroy the established biofilm. More importantly, methicillin-resistant Staphylococcus aureus (MRSA)-induced lung-infected mice can be effectively treated by the intravenous administration of N-arylimidazolium AMP mimic, which enable the design of N-arylimidazolium AMP mimics to offer an alternative avenue to eradicate drug-resistant bacterial infection.

ROS responsive nanoparticles loaded with lipid-specific AIEgen for atherosclerosis-targeted diagnosis and bifunctional therapy.

Atherosclerosis, which is triggered by endothelial damage, progressive local inflammation and excessive lipid accumulation, is one of the most common cardiovascular diseases in recent years. Drug delivery systems have shown great potential for the accurate diagnosis and effective treatment of early atherosclerosis, but are accompanied by disadvantages such as poor stability, lack of active targeting and non-specific recognition capabilities, which still need to be further developed. In our work, a multifunctional nanoparticle (LFP/PCDPD) with reactive oxygen species (ROS) responsive drug release, lipid removal, and lipid-specific AIE fluorescence imaging was constructed. Cyclodextrin structure with lipid removal function and PMEMA blocks with ROS-response-mediated hydrophobic to hydrophilic conversion were simultaneously introduced into the structure of LFP/PCDPD to load the anti-inflammatory drug prednisolone (Pred) and lipid-specific AIEgen (LFP). The active targeting function of LFP/PCDPD was conferred by the high affinity of dextran to the vascular adhesion molecule-1 (VCAM-1) and CD44 receptor on the surface of broken endothelial cells. After intravenous injection into ApoE-/- mice, LFP/PCDPD actively enriched in the microenvironment of local ROS overexpression and rich lipids in atherosclerosis. Pred and LFP were released while lipids were removed, thus enabling proactive targeting of atherosclerosis and efficient "two-pronged" treatment.

Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases.

Cardiovascular diseases have become the leading cause of death worldwide. The increasing burden of cardiovascular diseases has become a major public health problem and how to carry out efficient and reliable treatment of cardiovascular diseases has become an urgent global problem to be solved. Recently, implantable biomaterials and devices, especially minimally invasive interventional ones, such as vascular stents, artificial heart valves, bioprosthetic cardiac occluders, artificial graft cardiac patches, atrial shunts, and injectable hydrogels against heart failure, have become the most effective means in the treatment of cardiovascular diseases. Herein, an overview of the challenges and research frontier of innovative biomaterials and devices for the treatment of cardiovascular diseases is provided, and their future development directions are discussed.

A lipid droplet specific fluorescent probe for image-guided photodynamic therapy under hypoxia.

Photodynamic therapy (PDT) is a potential strategy for many superficial, esophageal, intestinal, and bronchial cancer treatments, but its therapeutic effect is limited by a lack of specificity and the hypoxic tumor environment. It is necessary to develop novel photosensitizers (Ps) with organelles targeting and the ability to generate cytotoxic species under light irradiation without the presence of oxygen. Herein, we designed and synthesized a biocompatible fluorescent Ps CPNBD for lipid droplets (LDs) fluorescence (FL) image-guided PDT. CPNBD showed FL quenching in water but FL was significantly turned on by oil with a remarkable FL enhancement compared to that in aqueous solution. Due to its strong lipophilicity (Clog P of 7.96), CPNBD could specifically stain the LDs of human clear cell renal cell carcinoma (ccRCC) tumor cells and tissues with good photostability. Meanwhile, CPNBD could efficiently generate cytotoxic reactive oxygen species under low-power white-light irradiation, which could efficiently damage DNA via a PDT process with great tumor suppression ability in vitro and in vivo. Thus, this work provides a novel strategy for designing LD-targeting Ps with efficient image-guided PDT under the tumor hypoxic environment.

Biomimetic-Coated Nanoplatform with Lipid-Specific Imaging and ROS Responsiveness for Atherosclerosis-Targeted Theranostics.

Atherosclerosis is one of the leading causes of cardiovascular diseases and is triggered by endothelial damage, local lipid cumulation, and inflammation. Despite the conventional medication treatment, nanosized drug carriers have become promising candidates for efficient drug delivery with lower side effects. However, the development of problems in nanocarriers such as drug leakage, accumulating efficiency, and accurate drug release, as well as the specific recognition of atherosclerotic plaques, still needs to be checked. In this study, a lipid-specific fluorophore (LFP) has been designed, which is further packaged with a reactive oxygen species (ROS)-responsive prednisolone (Pred) prodrug copolymer [PMPC-P(MEMA-co-PDMA)] to self-assemble into LFP@PMMP micelles. LFP@PMMP can be further coated with red blood cell (RBC) membrane to obtain surface-biomimetic nanoparticles (RBC/LFP@PMMP), demonstrating prolonged circulation, minimal drug leakage, and better accumulation at the plaques. With ROS responsiveness, RBC/LFP@PMMP can be interrupted at inflammatory atherosclerotic tissue with overexpressed ROS, followed by the dissociation of Pred from the polymer backbone and the release of LFP to combine with the rich lipid in the plaques. An accurate anti-inflammation and lipid-specific fluorescent imaging of atherosclerotic lesions was performed and further proven on ApoE-/- mice; this holds prospective potential for atherosclerosis theranostics.

Turn-on fluorescent probe for lipid droplet specific imaging of fatty liver and atherosclerosis.

Fluorescence imaging plays an important role in researching the biological function of lipid droplets (LDs). However, the short-wave emission, tedious synthesis process and insufficient specificity have significantly limited the applications of commercially available probes. Herein, we have prepared a novel one-step synthesized near-infrared (NIR) fluorescent probe, TNBD, with a very low emission in aqueous solution and the solid state, but a significantly enhanced fluorescence emission is exhibited in oleic acid. Moreover, TNBD exhibited an impressive lipid droplet (LD) specific fluorescence turn-on ability in cells, fatty liver and atherosclerosis (AS) samples with a good biocompatibility and high signal-to-noise ratio. Our study not only establishes a novel LD turn-on fluorescence probe, but also provides a novel way to prepare a NIR LD targeted fluorescence probe.

A bioprosthetic heart valve cross-linked by a non-glutaraldehyde reagent with improved biocompatibility, endothelialization, anti-coagulation and anti-calcification properties.

Valvular heart disease is an important disease that endangers human health and heart valve replacement has become one of the main treatments for patients with severe valvular heart disease. However, the traditional surgical valve replacement (SVR) suffers several drawbacks such as high risk, great trauma and long recovery time, and more than 30% of patients are intolerant to SVR, especially elderly patients. In recent years, with the development of minimally invasive technology, transcatheter heart valve replacement (THVR) as a method of implantation without thoracotomy has become an optimal treatment for severe valvular heart disease due to its advantages of minimal trauma, low risk and fast recovery. Meanwhile, the usage of bioprosthetic heart valves (BHVs) has been enlarged greatly with the rapid development of THVR and the aging population. Most BHVs in clinics are crosslinked by glutaraldehyde (Glut), which shows great mechanical properties and chemical stability. However, some problems such as poor biocompatibility, calcification, coagulation and endothelialization difficulty also need to be solved urgently for Glut-treated BHVs. In this work, a non-Glut treated BHV from 7a-ethyltetrahydro-oxazolo[3,4-c]oxazole (OX-Et) crosslinked porcine pericardium (PP) has been developed. Compared with glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good physical and chemical properties similar to Glut-PP are shown for OX-Et treated porcine pericardium (OX-Et-PP). It is noteworthy that better biocompatibility, endothelialization performance, and anti-coagulant effect as well as the improved anti-calcification property can also be observed for OX-Et-PP in the in vitro and in vivo study, potentially making OX-Et-PP a good candidate in the application of BHVs.

ROS Responsive Nanoplatform with Two-Photon AIE Imaging for Atherosclerosis Diagnosis and "Two-Pronged" Therapy.

Atherosclerosis, characterized by endothelial injury, progressive inflammation, and lipid deposition, can cause cardiovascular diseases. Although conventional anti-inflammatory drugs reveal a certain amount of therapeutic effect, more reasonable design on plaque targeting, local anti-inflammation, and lipid removal are still required for comprehensive atherosclerosis therapy. In this work, a theranostic nanoplatform is developed for atherosclerosis recognition and inhibition. A two-photon aggregation-induced emission (AIE) active fluorophore (TP) developed is linked to ß-cyclodextrin (CD) with a ROS responsive bond, which can carry prednisolone (Pred) in its entocoele via supramolecular interaction to build a diagnosis-therapy compound two-photon fluorophore-cyclodextrin/prednisolone complexes (TPCDP). With TPCDP packaged by nanosized micelles based on a ROS sensitive copolymer poly (2-methylthio ethanol methacrylate)-poly (2-methacryloyloxyethyl phosphorylcholine), the TPCDP@PMM can accumulate in atherosclerotic tissue through the damaged vascular endothelium. Activated by the local overexpressed ROS and rich lipid, the micelles are interrupted and TPCDP is further disintegrated with Pred release due to the relatively stronger interaction of lipid with CD, resulting in anti-inflammatory activity and lipid removal for atherosclerosis inhibition. Besides, labeled with the TP, TPCDP@PMM indicates a distinct two-photon AIE imaging on atherosclerosis recognition. The "two-pronged" therapeutic effect and plaque location ability has been confirmed in vivo on ApoE-/- mice, holding TPCDP@PMM a great promise for atherosclerosis theranostics.

pH and singlet oxygen dual-responsive GEM prodrug micelles for efficient combination therapy of chemotherapy and photodynamic therapy.

Nanocarriers have been an important strategy for enhancing the combination therapy of chemotherapy and photodynamic therapy (PDT) (Chem-PDT). However, conventional nanocarriers suffer from the problems of drug leakage in blood and insufficient drug release at target sites. Herein, we have designed a chlorin e6 (Ce6)-loaded GEM prodrug polymer micelle with a singlet oxygen cleavable linker and a pH responsive switch to avoid drug leakage in blood. These Ce6-loaded prodrug micelles possessed a uniform size distribution with a particle size of 78 nm. Meanwhile, the release of Ce6 and GEM was well controlled by acidic pH and laser irradiation. In addition, these micelles showed great acid triggered particle size shrinkage and charge-conversion properties, promoting micelle penetration at tumors and cellular uptake of micelles, which were confirmed by using CLSM of in vitro cell spheres and flow cytometry. Moreover, the in vitro and in vivo1O2 generation ability and antitumor ability of these micelles were impressive. This novel nanocarrier is a potential candidate for efficient Chem-PDT therapy.

Reactive Oxygen Species Responsive Theranostic Nanoplatform for Two-Photon Aggregation-Induced Emission Imaging and Therapy of Acute and Chronic Inflammation.

Inflammation is a protective response to stimuli trauma, which can also lead to severe tissue injury. The existing anti-inflammatory drugs, such as corticosteroids and glucocorticoids, generally exhibit side effects and poor accumulation in inflammatory tissue. Hence, a theranostic nanoplatform with serial reactive oxygen species (ROS) responsiveness and two-photon AIE bioimaging has been constructed for dimensional diagnosis and accurate therapy of inflammation. Prednisolone (Pred) is bridged to a two-photon fluorophore (TP) developed by us via a ROS sensitive bond to form a diagnosis-therapy compound TPP, which is then loaded by the amphipathic polymer PMPC-PMEMA (PMM) through self-assembling into the core-shell structured micelles (TPP@PMM). With a particle size of 57.5 nm, TPP@PMM can realize the accumulation in the inflammatory site via the oedematous tissue and the accurate release of anti-inflammatory drug Pred through the serial response to the local overexpressed ROS. The micellar structure is first interrupted by the ROS triggered hydrophobic-to-hydrophilic conversion of PMEMA, which allows the release of TPP. Then the ROS responsive bond in TPP is subsequently broken, resulting in the accurate delivery of Pred and the inflammation therapy. Furthermore, TPP@PMM can be traced in vivo with a distinct two-photon imaging due to the AIE active fluorophore TP. The theranostic TPP@PMM reveals high-resolution inflammation diagnosis and efficient anti-inflammatory activity owing to the two-photon fluorophore and the serial ROS responsiveness and has been proven to achieve the efficient treatment of acute lung injury, arthritis, and atherosclerosis. Therefore, TPP@PMM holds considerable promise as a potential strategy for acute and chronic inflammation theranostics.

Multi-stimuli responsive polymeric prodrug micelles for combined chemotherapy and photodynamic therapy.

Nowadays, cancer therapy faces severe challenges regarding boosting therapeutic efficiency and reducing the side effects of drugs. To overcome these challenges, herein multifunctional polymeric prodrug micelles combining chemotherapy and photodynamic therapy are put forward; the multifunctional polymeric prodrug micelles are prepared through self-assembly of amphipathic copolymer and photosensitizer Chlorin e6 (Ce6). These therapeutic prodrug micelles have better intracellular uptake and deeper tumor infiltration through charge reversal and smaller size changes, respectively. The polymeric prodrug micelles have fast disassembly and release Ce6 in the case of cathepsin B existence in the lysosome. Under light irradiation at 660 nm, Ce6 can efficiently generate singlet oxygen and accelerate the release of gemcitabine (GEM) by destroying the bis-(alkylthio) alkene functional group, which is the singlet-oxygen responsive linker, to achieve the combination of chemotherapy and photodynamic therapy (PDT). Under light irradiation at 660 nm, the singlet oxygen can also efficiently destroy mitochondrial functions to activate mitochondria apoptosis pathways, including increased reactive oxygen species (ROS) levels and swollen mitochondria. Further, employing 4T1-bearing BALB/c mice as a model, the anticancer effect of the therapeutic prodrug micelles is systematically investigated in vivo. The therapeutic prodrug micelles show an efficient tumor growth inhibition in vivo after light irradiation. Meanwhile, therapeutic prodrug micelles can significantly reduce adverse effects compared with the free drug, exhibiting better biocompatibility. Therefore, this prodrug micelle with a triple sensitivity response and synergistic chemo-photodynamic therapy functions is expected to offer promising applications in efficient antitumor therapy.

Integrated prodrug micelles with two-photon bioimaging and pH-triggered drug delivery for cancer theranostics.

Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging, less side effect, better drug utilization as well as the good bioimaging ability. However, traditional nanocarriers still suffer from unexpectable drug leakage, unsatisfactory tumor-targeted drug delivery and shallow imaging depth, which limit their further application in cancer theranostics. In this study, an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging, charge reversal and drug delivery triggered by acidic pH. The prodrug micelles can be self-assembled by the TP-PEI (DA/DOX)-PEG prodrug polymer, which consists of the two-photon fluorophore (TP), dimethylmaleic anhydride (DA) grafted polyethyleneimine (PEI) and polyethylene glycol (PEG). The PEG segment, DOX and DA are bridged to polymer by acid cleavable bonds, which provides the micelles a 'stealth' property and a satisfactory stability during blood circulation, while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment, thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery. The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo. Meanwhile, these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 µm in depth. The great antitumor efficacy, reduced side effect and deep two-photon tissue imaging make the TP-PEI (DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.