An AIEgen and Iodine Double-Ornamented Platinum(II) Complex for Bimodal Imaging-Guided Chemo-Photodynamic Combination Therapy.

Real-time biodistribution monitoring and enhancing the therapeutic efficacy of platinum(II)-based anticancer drugs are urgently required to elevate their clinical performance. Herein, a tetraphenylethene derivative (TP) with aggregation-induced emission (AIE) properties and an iodine atom are selected as ligands to endow platinum (II) complex TP-Pt-I with real-time in vivo self-tracking ability by fluorescence (FL) and computerized tomography (CT) imaging, and improved anticancer efficacy by the combination of chemotherapy and photodynamic therapy. Especially, benefiting from the formation of a donor-acceptor-donor structure between the AIE photosensitizer TP and Pt-I moiety, the heavy atom effects of Pt and I, and the presence of I, TP-Pt-I displayed red-shifted absorption and emission wavelengths, enhanced ROS generation efficiency, and improved CT imaging capacity compared with the pristine TP and the control agent TP-Pt-Cl. As a result, the enhanced intratumoral accumulation of TP-Pt-I loaded nanoparticles is readily revealed by dual-modal FL and CT imaging with high contrast. Meanwhile, the TP-Pt-I nanoparticles show significantly improved tumor growth-inhibiting effects on an MCF-7 xenograft murine model by combining the chemotherapeutic effects of platinum(II) and the photodynamic effects of TP. This self-tracking therapeutic complex thus provides a new strategy for improving the therapeutic outcomes of platinum(II)-based anticancer drugs.

CD44-targeting hyaluronic acid-selenium nanoparticles boost functional recovery following spinal cord injury.

BACKGROUND: Therapeutic strategies based on scavenging reactive oxygen species (ROS) and suppressing inflammatory cascades are effective in improving functional recovery after spinal cord injury (SCI). However, the lack of targeting nanoparticles (NPs) with powerful antioxidant and anti-inflammatory properties hampers the clinical translation of these strategies. Here, CD44-targeting hyaluronic acid-selenium (HA-Se) NPs were designed and prepared for scavenging ROS and suppressing inflammatory responses in the injured spinal cord, enhancing functional recovery. RESULTS: The HA-Se NPs were easily prepared through direct reduction of seleninic acid in the presence of HA. The obtained HA-Se NPs exhibited a remarkable capacity to eliminate free radicals and CD44 receptor-facilitated internalization by astrocytes. Moreover, the HA-Se NPs effectively mitigated the secretion of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) by microglia cells (BV2) upon lipopolysaccharide-induced inflammation. In vivo experiments confirmed that HA-Se NPs could effectively accumulate within the lesion site through CD44 targeting. As a result, HA-Se NPs demonstrated superior protection of axons and neurons within the injury site, leading to enhanced functional recovery in a rat model of SCI. CONCLUSIONS: These results highlight the potential of CD44-targeting HA-Se NPs for SCI treatment.

Thiol-Responsive Polypeptide Sulfur Dioxide Prodrug Nanoparticles for Effective Tumor Inhibition.

Sulfur dioxide (SO2) based gas therapy has emerged as a novel anticancer therapeutic strategy because of its high therapeutic efficacy and biosafety. To precisely adjust the SO2 content and control gas release, herein, a thiol-responsive polypeptide SO2 prodrug mPEG-block-poly(2-amino-6-(2,4-dinitrophenylsulfonamido)hexanoic acid) (PEG-b-PLys-DNs) was designed and facilely synthesized by polymerization of a novel N-carboxyanhydride SO2-NCA. The anticancer potential of the self-assembled nanoparticles (SO2-NPs) was investigated in detail. First, PEG-b-PLys-DNs were synthesized by ring-opening polymerization of SO2-NCA, which self-assembled into NPs sized 88.4 nm in aqueous. Subsequently, SO2-NPs were endocytosed into 4T1 cells and quickly released SO2 under a high concentration of glutathione in tumor cells. This process depleted cellular glutathione, generated reactive oxygen species, and dramatically increased oxidative stress, which led to cancer cell apoptosis. Finally, the in vivo anticancer efficacy of SO2-NPs was verified in 4T1-tumor-bearing mice. Our results indicated that this novel SO2 polymeric prodrug has great potential in eradicating tumors.

A Two-In-One Nanoprodrug for Photoacoustic Imaging-Guided Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) is garnering considerable attention in cancer treatment due to its non-invasive nature and the potential of spatiotemporal control. However, the high level of glutathione (GSH) in cancer cells can alleviate the SDT-mediated ROS-damages, resulting in a reduced SDT effect. Here, a two-in-one nano-prodrug for photoacoustic imaging-guided enhanced SDT against skin cancers is synthesized. A dual-prodrug molecule (DOA) of sulfide dioxide (SO2 ) and 5-aminolevulinic acid (ALA) is first synthesized and then co-assembled with methoxyl poly(ethylene glycol)-b-poly(l-lysine) (mPEG-b-PLL) to generate the two-in-one prodrug nanoparticles (P-DOA NPs). The P-DOA NPs simultaneously released ALA and SO2 in response to the overexpressed GSH in tumor cells. The released ALA is metabolically converted into protoporphyrin IX (PpIX) in tumor cells for SDT and photoacoustic imaging. Meanwhile, the released SO2 , together with the consumption of GSH based on the reaction of DOA in P-DOA NPs with intracellular GSH, can significantly increase the intracellular ROS content, leading to enhanced SDT. As a result, the P-DOA NPs significantly inhibited the growth of melanoma and squamous cell carcinoma xenografts in mouse models under the guidance of real-time photoacoustic imaging. Therefore, this novel two-in-one nano-prodrug is promising for effective SDT against skin cancers.

Polymeric nanomedicines for the treatment of hepatic diseases.

The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.

Monomer Controlled Switchable Copolymerization: A Feasible Route for the Functionalization of Poly(lactide).

Switchable polymerization is an attractive strategy to enable the sequential selectivity of multi-block polyesters. Besides, these well-defined multi-block polyesters could enable further modification for wider applications. Herein, based on the reversible insertion of CO2 by Salen-MnIII , a new monomer controlled self-switchable polymerization route was developed. Chemoselective ring opening copolymerization of O-carboxyanhydrides (OCAs) and lactide (LA) was explored without cocatalyst. The sequential conversion of OCAs and LA into the polymer chain could form multi-block polyesters. Based on this strategy, a series of multi-block polyesters with different pendant groups were synthesized. Furthermore, by modifying the propargyl-containing copolymers with quaternary ammonium groups, we have realized antibacterial functionalization of PLA. These results imply the potential application of this strategy for the fabrication of functional polymers for biomedical applications.

2-Phenyl-3-(p-aminophenyl) Acrylonitrile: A Reactive Matrix for Sensitive and Selective Analysis of Glycans by MALDI-MS.

Analysis of glycans by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is usually limited by the intrinsically low abundance and low ionization efficiency of glycans. Aiming to enhance the ionization efficiency of glycans and simplify the sample preparation procedure during MALDI-MS analysis, we reported herein a novel reactive matrix, 2-phenyl-3-(p-aminophenyl) acrylonitrile (PAPAN), for sensitive and selective detection of glycans. PAPAN is a derivative of α-cyanocinnamic acid, which possesses high ionization efficiency in MALDI-MS. The PAPAN can react with the terminal aldehyde of glycans and thereby enable the significant enhancement of ionization efficiency of glycans. As a result, using PAPAN as a reactive matrix, the detection sensitivity for glycans was improved 100-fold compared with that using 2,5-dihydroxybenzoic acid (DHB) as the matrix. Meanwhile, the ionization of peptides can be significantly suppressed using PAPAN as the matrix, which allowed the selective detection of N-glycans from a deglycosylated tryptic digest of glycoprotein without any prepurification. Moreover, the PAPAN matrix also endowed the analysis of glycans with enhanced fragmentation during MS/MS analysis, which could facilitate glycan structure interpretation. Finally, PAPAN was successfully used for the analysis of N-glycome in human serum. Thus, a simple, sensitive, and selective method for the analysis of glycans has been achieved by using a novel reactive matrix, PAPAN.

Synthesis of Y-Shaped OEGylated Poly(amino acid)s: The Impact of OEG Architecture.

OEGylation is an attractive approach to modifying poly(amino acid)s. OEG conjugation improves water-solubility of poly(amino acid)s, and confers possible thermal-responsive functionality for the conjugated poly(amino acid)s. Nevertheless, the impact of OEG architecture and the manner in which the OEG moiety interferes with the performances of poly(amino acid)s remain a work in progress. In this study, a series of new linear and Y-shaped OEG-substituted poly(glutamic acid)s were designed and synthesized. It is found that the thermoresponsive behavior of OEGylated poly(glutamic acid)s experiences steric repulsion effect, the strengths of which are architecture and length-dependent, and grows pronounced only when the number of the OEG units is ≥6. Notably, the Y-shaped architecture is able to stabilize the helicity of poly(glutamic acid) backbones, while maintaining higher α-helical conformation than its linear counterparts. In sum, our result indicate that Y-shaped architecture is more appropriate toward OEGylating poly(amino acid)s for biomedical applications.

A Multifunctional Polypeptide via Ugi Reaction for Compact and Biocompatible Quantum Dots with Efficient Bioconjugation.

The growing application of quantum dots (QDs) in biomedical research necessitates, in turn, continuous development of surface functionalizing ligands to optimize their performance for ever more challenging and diverse biological applications. Here, we demonstrate the novel multifunctional polypeptide ligands for compact and biocompatible QDs. The target ligand preparation exploits the efficient, activating agent-free Ugi reaction of four functional components to incorporate lipoic acid, pyridine, zwitterion motifs, and reactive functionalities in a one-pot procedure under mild conditions. Cap exchange with these multifunctional polypeptide ligands generates hydrophilic QD dispersions, which are colloidally stable for prolonged periods of time. The zwitterionic ligation delivers compact and small QDs, and the existence of reactive functionalities enables coupling of the QDs to biologics through bio-orthogonal coupling chemistry, such as ligation of azide-modified QDs to DNA. Therefore, this QD functionalization strategy via Ugi reaction is believed to be a viable approach for compact and biocompatible QDs with efficient bioconjugation.

PEGylated Poly(α-lipoic acid) Loaded with Doxorubicin as a pH and Reduction Dual Responsive Nanomedicine for Breast Cancer Therapy.

Disulfide-containing nanoparticles are promising vehicles for anticancer drug delivery. However, the preparation of disulfide-containing nanoparticles usually relies on complex synthetic procedures. In the present work, a PEGylated poly(α-lipoic acid) (mPEG-PαLA) copolymer was facilely synthesized and used for pH and reduction dual responsive drug delivery. Poly(α-lipoic acid) was prepared by thermal polymerization of α-lipoic acid without any catalyst or solvent and then conjugated with methoxy poly(ethylene glycol) to form the mPEG-PαLA copolymer. The obtained mPEG-PαLA copolymer was amphiphilic, which could self-assemble into nanoparticles (NPs) in aqueous solution. More interestingly, the mPEG-PαLA NPs showed high drug loading efficiency (87.7%) for the cationic drug doxorubicin (DOX). The DOX-loaded NPs (NPs-DOX) exhibited pH and reduction dual responsive drug release behaviors. Moreover, the flow cytometry analysis and confocal laser scanning microscopy confirmed that the drug-loaded nanoparticles could be efficiently internalized and subsequently release DOX in 4T1 cancer cells. As a result, the NPs-DOX displayed favorable antiproliferation efficacy in 4T1 cancer cells (measured by MTT assays). Furthermore, the NPs-DOX showed enhanced antitumor efficacy in a 4T1 tumor-bearing mice model with reduced side toxicities toward normal organs due to the prolonged circulation time and improved biodistribution in vivo. In other words, this work demonstrates that the PEGylated poly(α-lipoic acid) copolymer can be used as a biocompatible and stimuli-responsive nanocarrier for anticancer drug delivery, which may have potential clinical utility.

Injectable Enzymatically Cross-linked Hydrogels with Light-Controlled Degradation Profile.

An advanced hydrogel that features facile formation and injectability as well as light-controlled degradation profile is reported here. By modifying 4-arm poly(ethylene glycol) (4-arm PEG) with 2-nitrobenzyl (NB) and phenol, the 4-arm PEG precursor solutions could form enzymatically cross-linked hydrogels in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2 O2 ). The gelation time, mechanical strength, and porous structure could be simply tuned by the concentration of HRP and H2 O2 . Moreover, the hydrogels underwent controlled degradation under UV light irradiation via photo-cleavage reaction of the NB ester bond. The hydrogels exhibited negligible cytotoxicity toward mouse fibroblast L929 cells in vitro and can be manipulated through injection in vivo.

Multi-Sensor Based Online Attitude Estimation and Stability Measurement of Articulated Heavy Vehicles.

Articulated wheel loaders used in the construction industry are heavy vehicles and have poor stability and a high rate of accidents because of the unpredictable changes of their body posture, mass and centroid position in complex operation environments. This paper presents a novel distributed multi-sensor system for real-time attitude estimation and stability measurement of articulated wheel loaders to improve their safety and stability. Four attitude and heading reference systems (AHRS) are constructed using micro-electro-mechanical system (MEMS) sensors, and installed on the front body, rear body, rear axis and boom of an articulated wheel loader to detect its attitude. A complementary filtering algorithm is deployed for sensor data fusion in the system so that steady state margin angle (SSMA) can be measured in real time and used as the judge index of rollover stability. Experiments are conducted on a prototype wheel loader, and results show that the proposed multi-sensor system is able to detect potential unstable states of an articulated wheel loader in real-time and with high accuracy.

Injectable Polypeptide Hydrogel as Biomimetic Scaffolds with Tunable Bioactivity and Controllable Cell Adhesion.

Injectable hydrogels have been widely investigated for applications in biomedical fields, for instance, as biomimetic scaffolds mimicking the extracellular matrix (ECM). In addition to as scaffolds for mechanical support and transferring of nutrients, the dynamic bioactivity of ECM is another critical factor that affects cell behavior. In this work, a novel injectable poly(l-glutamic acid)-based hydrogel decorated with RGD was fabricated. The presentation of RGD significantly enhanced the cell-matrix interaction and promoted cell adhesion and proliferation. Moreover, the cell-adhesive RGD was conjugated to the network via a disulfide bond, so that the density of RGD and the bioactivity of hydrogel can be well controlled by tuning the RGD content through treating with glutathione. As a result, the cell behaviors on the hydrogel can be tuned on demand. The injectable hydrogel with controllable bioactivity may provide an interesting strategy to develop a scaffold mimicking ECM that can regulate cell adhesion dynamically.

Multidentate Comb-Shaped Polypeptides Bearing Trithiocarbonate Functionality: Synthesis and Application for Water-Soluble Quantum Dots.

We describe here the synthesis of multidentate comb-shaped polypeptides bearing trithiocarbonate functionality and their application in the preparation of water-soluble quantum dots (QDs). A new l-lysine-based N-carboxyanhydride monomer containing trithiocarbonate functionality was designed and synthesized. Ring-opening polymerization of the resulting monomer initiated by hexamethyldisilazane affords polypeptides bearing pendent trithiocarbonate groups (P(TTCLys)) with controllable molecular weights. P(TTCLys) was then applied to mediate the reversible addition-fragmentation chain-transfer polymerization of oligo(ethylene glycol)acrylate for the metal-free preparation of hydrophilic comb-shaped polypeptides. Simple reduction of trithiocarbonate functionality enabled the introduction of multiple thiol anchoring groups to the above-mentioned comb-shaped polypeptides. Finally, the obtained multidentate polypeptide-based ligands were successfully applied in the ligand exchange procedures to generate water-soluble QDs. The fluorescent microscopic images suggested that the resultant water-soluble QDs could be effectively internalized into HeLa cells to realize bright cellular imaging. Therefore, our work can result in a new kind of valuable polypeptide-based QDs with hydrophilic character and biocompatibility for cellular imaging.

Recent advances in sulfur dioxide releasing nanoplatforms for cancer therapy.

Sulfur dioxide (SO2), long considered to be a harmful atmospheric pollutant, has recently been posited as the fourth gasotransmitter, as it is produced endogenously in mammals and has important pathophysiological effects. The field of tumor therapy has witnessed a paradigm shift with the emergence of SO2-based gas therapy. This has been possible because SO2 is a potent glutathione consumer that can promote the production of reactive oxygen species, eventually leading to oxidative-stress-induced cancer cell death. Nevertheless, this therapeutic gas cannot be directly administrated in gaseous form. Thus, various nano formulations incorporating SO2 donors or prodrugs capable of storing and releasing SO2 have been developed in an attempt to achieve active/passive intratumoral accumulation and SO2 release in the tumor microenvironment. In this review article, the advances over the past decade in nanoplatforms incorporating sulfur SO2 prodrugs to provide controlled release of SO2 for cancer therapy are summarized. We first describe the synthesis of polypeptide SO2 prodrugs to overcome multiple drug resistance that was pioneered by our group, followed by other macromolecular SO2 prodrug structures that self-assemble into nanoparticles for tumor therapy. Second, we describe nanoplatforms composed of various small-molecule SO2 donors with endogenous or exogenous stimuli responsiveness, including thiol activated, acid-sensitive, and ultraviolet or near-infrared light-responsive SO2 donors, which have been used for tumor inhibition. Combinations of SO2 gas therapy with photodynamic therapy, chemotherapy, photothermal therapy, sonodynamic therapy, and nanocatalytic tumor therapy are also presented. Finally, we discuss the current limitations and challenges and the future outlook for SO2-based gas therapy. STATEMENT OF SIGNIFICANCE: Gas therapy is attracting increasing attention in the scientific community because it is a highly promising strategy against cancer owing to its inherent biosafety and avoidance of drug resistance. Sulfur dioxide (SO2) is recently found to be produced endogenously in mammals with important pathophysiological effects. This review summarizes recent advances in SO2 releasing nanosystems for cancer therapy, including polymeric prodrugs, endogenous or exogenous stimulus-activated SO2 donors delivered by nanoplatform and combination therapy strategies.

Advances in Hydrogels for Periodontitis Treatment.

Periodontitis is a common condition characterized by a bacterial infection and the disruption of the body's immune-inflammatory response, which causes damage to the teeth and supporting tissues and eventually results in tooth loss. Current therapy involves the systemic and local administration of antibiotics. However, the existing treatments cannot exert effective, sustained release and maintain an effective therapeutic concentration of the drug at the lesion site. Hydrogels are used to treat periodontitis due to their low cytotoxicity, exceptional water retention capability, and controlled drug release profile. Hydrogels can imitate the extracellular matrix of periodontal cells while offering suitable sites to load antibiotics. This article reviews the utilization of hydrogels for periodontitis therapy based on the pathogenesis and clinical manifestations of the disease. Additionally, the latest therapeutic strategies for smart hydrogels and the main techniques for hydrogel preparation have been discussed. The information will aid in designing and preparing future hydrogels for periodontitis treatment.

A Nanoscale Trans-Platinum(II)-Based Supramolecular Coordination Self-Assembly with a Distinct Anticancer Mechanism.

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl2(pyridine)(NH3)] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.

Proanthocyanidins-based tandem dynamic covalent cross-linking hydrogel for diabetic wound healing.

Wound healing in diabetic patients presents significant challenges in clinical wound care due to high oxidative stress, excessive inflammation, and a microenvironment prone to infection. In this study, we successfully developed a multifunctional tandem dynamic covalently cross-linked hydrogel dressing aimed at diabetic wound healing. This hydrogel was constructed using cyanoacetic acid functionalized dextran (Dex-CA), 2-formylbenzoylboric acid (2-FPBA) and natural oligomeric proanthocyanidins (OPC), catalyzed by histidine. The resulting Dex-CA/OPC/2-FPBA (DPOPC) hydrogel can be dissolved triggered by cysteine, thereby achieving "controllable and non-irritating" dressing change. Furthermore, the incorporation of OPC as a hydrogel building block endowed the hydrogel with antioxidant and anti-inflammatory properties. The cross-linked network of the DPOPC hydrogel circumvents the burst release of OPC, enhancing its biosafety. In vivo studies demonstrated that the DPOPC hydrogel significantly accelerated the wound healing process in diabetic mice compared to a commercial hydrogel, achieving an impressive wound closure rate of 98 % by day 14. The DPOPC hydrogel effectively balanced the disrupted inflammatory state during the healing process. This dynamic hydrogel based on natural polyphenols is expected to be an ideal candidate for dressings intended for chronic wounds.

In Situ Reaction-Generated Aldehyde-Scavenging Polypeptides-Curcumin Conjugate Nanoassemblies for Combined Treatment of Spinal Cord Injury.

The microenvironment after traumatic spinal cord injury (SCI) involves complex pathological processes, including elevated oxidative stress, accumulated reactive aldehydes from lipid peroxidation, excessive immune cell infiltration, etc. Unfortunately, most of current neuroprotection therapies cannot cope with the intricate pathophysiology of SCI, leading to scant treatment efficacies. Here, we developed a facile in situ reaction-induced self-assembly method to prepare aldehyde-scavenging polypeptides (PAH)-curcumin conjugate nanoassemblies (named as PFCN) for combined neuroprotection in SCI. The prepared PFCN could release PAH and curcumin in response to oxidative and acidic SCI microenvironment. Subsequently, PFCN exhibited an effectively neuroprotective effect through scavenging toxic aldehydes as well as reactive nitrogen and oxygen species in neurons, modulating microglial M1/M2 polarization, and down-regulating the expression of inflammation-related cytokines to inhibit neuroinflammation. The intravenous administration of PFCN could significantly ameliorate the malignant microenvironment of injured spinal cord, protect the neurons, and promote the motor function recovery in the contusive SCI rat model.

Immunosuppressive enzyme-responsive nanoparticles for enhanced accumulation in liver allograft to overcome acute rejection.

Acute rejection is a life-threatening complication after liver transplantation. Immunosuppressants such as tacrolimus are used to inhibit acute rejection of liver grafts in clinic. However, inefficient intragraft accumulation may reduce the therapeutic outcomes of tacrolimus. Here, an enzyme-responsive nanoparticle is developed to selectively enhance the accumulation of tacrolimus in liver allograft through enzyme-induced aggregation to refine immunotherapeutic efficacy of tacrolimus. The nanoparticles are composed of amphiphilic tacrolimus prodrugs synthesized by covalently conjugating tacrolimus and matrix metalloproteinase 9 (MMP9)-cleavable peptide-containing methoxy poly (ethylene glycol) to poly (l-glutamic acid). Upon exposure to MMP9, which is overexpressed in rejected liver allografts, the nanoparticles undergo a morphological transition from spherical micellar nanoparticles to microscale aggregate-like scaffolds. Intravenous administration of MMP9-responsive nanoparticles into a rat model of acute liver graft rejection results in enhanced nanoparticle accumulation in allograft as compared to nonresponsive nanoparticles. Consequently, the MMP9-responsive nanoparticles significantly inhibit intragraft inflammatory cell infiltration and proliferation, maintain intragraft immunosuppressive environment, alleviate graft damage, improve liver allograft function, abate weight loss and prolong recipient survival. This work proves that morphology-switchable enzyme-responsive nanoparticles represent an innovative strategy for selectively enhancing intragraft accumulation of immunosuppressive agents to improve treatment of liver allograft rejection.