Untargeted Metabolome Analyses Revealed Potential Metabolic Mechanisms of Leymus chinensis in Response to Simulated Animal Feeding.

Leymus chinensis (Trin.) Tzvel., also known as the "Alkali Grass", is a major forage grass in the eastern and northeastern steppe vegetation in the Songnen Prairie. It is of great practical significance for grassland management to understand the influence of animal saliva on L. chinensis during animal feeding. In this study, we used clipping and daubing animal saliva to simulate responses to grazing by L. chinensis, and analyzed the physiological and metabolomic changes in response to simulated animal feeding. Results showed that the effects of animal saliva on physiological and metabolic processes of the treated plants produced a recovery phenomenon. Moreover, the effects of animal saliva produced a large number of differential metabolites related to several known metabolic pathways, among which the flavonoid biosynthesis pathway has undergone significant and persistent changes. We posit that the potential metabolic mechanisms of L. chinensis in response to simulated animal feeding are closely related to flavonoid biosynthesis.

Stimuli-responsive composite biopolymer actuators with selective spatial deformation behavior.

Bioinspired actuators with stimuli-responsive and deformable properties are being pursued in fields such as artificial tissues, medical devices and diagnostics, and intelligent biosensors. These applications require that actuator systems have biocompatibility, controlled deformability, biodegradability, mechanical durability, and stable reversibility. Herein, we report a bionic actuator system consisting of stimuli-responsive genetically engineered silk-elastin-like protein (SELP) hydrogels and wood-derived cellulose nanofibers (CNFs), which respond to temperature and ionic strength underwater by ecofriendly methods. Programmed site-selective actuation can be predicted and folded into three-dimensional (3D) origami-like shapes. The reversible deformation performance of the SELP/CNF actuators was quantified, and complex spatial transformations of multilayer actuators were demonstrated, including a biomimetic flower design with selective petal movements. Such actuators consisting entirely of biocompatible and biodegradable materials will offer an option toward constructing stimuli-responsive systems for in vivo biomedicine soft robotics and bionic research.

Liposomal Enzyme Nanoreactors Based on Nanoconfinement for Efficient Antitumor Therapy.

Enzymatic reactions can consume endogenous nutrients of tumors and produce cytotoxic species and are therefore promising tools for treating malignant tumors. Inspired by nature where enzymes are compartmentalized in membranes to achieve high reaction efficiency and separate biological processes with the environment, we develop liposomal nanoreactors that can perform enzymatic cascade reactions in the aqueous nanoconfinement of liposomes. The nanoreactors effectively inhibited tumor growth in vivo by consuming tumor nutrients (glucose and oxygen) and producing highly cytotoxic hydroxyl radicals (⋅OH). Co-compartmentalization of glucose oxidase (GOx) and horseradish peroxidase (HRP) in liposomes could increase local concentration of the intermediate product hydrogen peroxide (H2 O2 ) as well as the acidity due to the generation of gluconic acid by GOx. Both H2 O2 and acidity accelerate the second-step reaction by HRP, hence improving the overall efficiency of the cascade reaction. The biomimetic compartmentalization of enzymatic tandem reactions in biocompatible liposomes provides a promising direction for developing catalytic nanomedicines in antitumor therapy.

Confining the Sol-Gel Reaction at the Water/Oil Interface: Creating Compartmentalized Enzymatic Nano-Organelles for Artificial Cells.

Living organisms compartmentalize their catalytic reactions in membranes for increased efficiency and selectivity. To mimic the organelles of eukaryotic cells, we develop a mild approach for in situ encapsulating enzymes in aqueous-core silica nanocapsules. In order to confine the sol-gel reaction at the water/oil interface of miniemulsion, we introduce an aminosilane to the silica precursors, which serves as both catalyst and an amphiphilic anchor that electrostatically assembles with negatively charged hydrolyzed alkoxysilanes at the interface. The semi-permeable shell protects enzymes from proteolytic attack, and allows the transport of reactants and products. The enzyme-carrying nanocapsules, as synthetic nano-organelles, are able to perform cascade reactions when enveloped in a polymer vesicle, mimicking the hierarchically compartmentalized reactions in eukaryotic cells. This in situ encapsulation approach provides a versatile platform for the delivery of biomacromolecules.

Transient Hybridization Directed Nanoflare for Single-Molecule miRNA Imaging.

Accurate quantifications of cellular miRNAs are important not only for accelerating them becoming reliable diagnostics biomarkers but also for deeply understanding their influence on central signaling pathways. Although single-molecule miRNA imaging permits quantifying biomolecules at the single-molecule level, it is limited by the sensitivity and specificity of hybridization-based probes. We report a miRNA single-molecule imaging method by using conjugated polymer nanoparticle (CPN) labeled short DNA probe termed as a nanoflare. The transient hybridization of the nanoflares and target miRNAs yields a featured single-molecule kinetics signal rendering high single-molecule sensitivity and specificity. miRNA can be detected with a remarkable detection limit of 1 fM without using any amplification steps. The discrimination capability of homologous miRNAs was also demonstrated. Taking advantage of the featured single-molecule signal of the nanoflare, we can directly count single miR-21 molecules in single cells by using highly inclined and laminated optical sheet (HILO) microscopy. The statistics of the counting reveals miR-21's cell-to-cell fluctuation and differential expression of tumor cells and normal cells.

Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer.

Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(ε-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(ε-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tumors, spherical micelles as large as 300 nm in diameter were found to extravasate in the autochthonous model, reaching a distance of approximately 20 µm from the nearest tumor cell clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further able to achieve a ∼7-fold higher peak accumulation and a ∼50-fold increase in its retention half-life in pancreatic tumors when delivered with 100 nm long worm-like micelles as when compared to the free drug formulation of oxaliplatin. Through further engineering of nanoparticle properties, as well as by widespread adoption of the autochthonous tumor model for preclinical testing, future therapeutic formulations may further enhance the targeting and penetration of anticancer agents to improve survival outcomes in PDAC.

A non-enzymatic urine glucose sensor with 2-D photonic crystal hydrogel.

A novel polymerized crystalline colloidal array (PCCA) sensing material for the detection of urine glucose was developed by embedding a two-dimensional (2-D) polystyrene crystalline colloidal array (CCA) in 3-acrylamidophenylboronic acid (3-APBA)-functionalized hydrogel. After adjusting the cross-linker concentration, this material showed significant sensitivity for glucose under lab conditions, the particle spacing of the PCCA changed from 917 to 824 nm (93 nm) within 3 min as the glucose concentration increased from 0 to 10 mM, and the structural color of the PCCA changed from red through orange, to green, and finally, to cyan. In further experiments, this material was used to semi-quantitatively detect glucose in 20 human urine (HU) samples. Compared with the traditional dry-chemistry method, which was applied widely in clinical diagnosis, the PCCA method was more accurate and cost-effective. Moreover, this method can efficiently avoid the errors induced by most of the urine-interfering elements like vitamin C and ketone body. With a homemade portable optical detector, this low-cost intelligent sensing material can provide a more convenient and efficient strategy for the urine glucose detection in clinical diagnosis and point-of-care monitoring.

A Polyplatin with Hands-Holding Near-Infrared-II Fluorophores and Prodrugs at a Precise Ratio for Tracking Drug Fate with Realtime Readout and Treatment Feedback.

The in vivo fate of chemotherapeutic drugs plays a vital role in understanding the therapeutic outcome, side effects, and the mechanism. However, the lack of imaging abilities of drugs, tedious labeling processes, and premature leakage of imaging agents result in loss of fidelity between the drugs and imaging signals. Herein, an amphiphilic polymer is created by copolymerization of a near-infrared-II (NIR-II) fluorophore tracer (T) and an anticancer Pt(IV) prodrug (D) of cisplatin in a hand-holding manner into one polymer chain for the first time. The obtained PolyplatinDT is capable of delivering the drugs and the fluorophores concomitantly at a precise D/T ratio, thereby resulting in tracking the platinum drugs and even readout of them in real-time via NIR-II imaging. PolyplatinDT can self-assemble into nanoparticles, referred to as NanoplatinDT. Furthermore, a caspase-3 cleavable peptide that serves as an apoptosis reporter is attached to NanoplatinDT, resulting in NanoplatinDTR that are capable of simultaneously tracking platinum drugs and evaluating the therapeutic efficacy. Overall, it is reported here the design of the first theranostic polymer with anticancer drugs, drug tracers, and drug efficacy reporters that can work in concert to provide insight into the drug fate and mechanism of action.

Platinum Prodrug Nanoparticles with COX-2 Inhibition Amplify Pyroptosis for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer.

Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents can induce pyroptosis via caspase-3 activation. However, these agents also enhance cyclooxygenase-2 (COX-2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy-induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT-Pt-In) containing both indomethacin (In, a COX-2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self-assemble into nanoparticles (denoted as Pt-In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX-2 expression, hence overcoming the chemoresistance and amplifying cisplatin-induced pyroptosis. In a pancreatic cancer mouse model, Pt-In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti-programmed death ligand (α-PD-L1) treatment, Pt-In NP demonstrate the ability to completely suppress metastatic tumors, transforming "cold tumors" into "hot tumors". Overall, the sustained release of Pt(IV) and In from Pt-In NP amplifies platinum-drug-induced pyroptosis to elicit long-term immune responses, hence presenting a generalizable strategy for pancreatic cancer.

Organic-inorganic composite hydrogels: compositions, properties, and applications in regenerative medicine.

Hydrogels, formed from crosslinked hydrophilic macromolecules, provide a three-dimensional microenvironment that mimics the extracellular matrix. They served as scaffold materials in regenerative medicine with an ever-growing demand. However, hydrogels composed of only organic components may not fully meet the performance and functionalization requirements for various tissue defects. Composite hydrogels, containing inorganic components, have attracted tremendous attention due to their unique compositions and properties. Rigid inorganic particles, rods, fibers, etc., can form organic-inorganic composite hydrogels through physical interaction and chemical bonding with polymer chains, which can not only adjust strength and modulus, but also act as carriers of bioactive components, enhancing the properties and biological functions of the composite hydrogels. Notably, incorporating environmental or stimulus-responsive inorganic particles imparts smartness to hydrogels, hence providing a flexible diagnostic platform for in vitro cell culture and in vivo tissue regeneration. In this review, we discuss and compare a set of materials currently used for developing organic-inorganic composite hydrogels, including the modification strategies for organic and inorganic components and their unique contributions to regenerative medicine. Specific emphasis is placed on the interactions between the organic or inorganic components and the biological functions introduced by the inorganic components. The advantages of these composite hydrogels indicate their potential to offer adaptable and intelligent therapeutic solutions for diverse tissue repair demands within the realm of regenerative medicine.

Biodegradable Polymer with Effective Near-Infrared-II Absorption as a Photothermal Agent for Deep Tumor Therapy.

Photothermal therapy holds great promise for cancer treatment due to its effective tumor ablation and minimal invasiveness. Herein a new class of biodegradable photothermal agents with effective adsorption in both near-infrared-I (NIR-I) and NIR-II windows is reported for deep tumor therapy. As demonstrated in a deep-seated ovarian cancer model, photothermal therapy using 1064 nm irradiation effectively inhibits tumor progression and prolongs survival spans. This work provides a new design of photothermal agents toward a more effective therapy of tumors.

Microneedle-based two-step transdermal delivery of Langerhans cell-targeting immunoliposomes induces a Th1-biased immune response.

Novel Coronavirus is affecting human's life globally and vaccines are one of the most effective ways to combat the epidemic. Transcutaneous immunization based on microneedle (MN) has attracted much attention because of its painlessness, rapidity, high efficiency and good compliance. In this study, CD11c monoclonal antibody-immunoliposomes (OVA@CD11c-ILP) actively targeting to Langerhans cells (LCs) were successfully prepared and were delivered by the microchannels of skin produced by MN to induce an immune response in vivo. OVA@CD11c-ILP could be targeted to LCs by conjugating CD11c monoclonal antibody to the surface of the ILP. OVA@CD11c-ILP promoted the maturation of dendritic cells (DCs) and the uptake and endocytosis of antigen by LCs. Moreover, OVA@CD11c-ILP immunization can significantly inhibit tumor growth and prolong overall survival. Furthermore, a higher antibody's titer ratio of IgG1/IgG2a indicated that the immune response stimulated by this immunization method was Th1-biased and the liposomes showed Th1-type adjuvant effect. In conclusion, the combination delivery system of immunoliposomes and microneedle can significantly improve the efficiency of antigen presentation and effectively activate cellular immune responses in the body, which is expected to be a promising transdermal immune strategy.

Improving antibacterial performance of dental resin adhesive via co-incorporating fluoride and quaternary ammonium.

OBJECTIVE: Aiming to achieve improved antibacterial performance for dental application, sodium fluoride (NaF) nanoparticles and photopolymerizable N,N-dodecylvinylimidazole (DCV) were co-introduced into the dental resin adhesive at different ratios. METHODS: The respective effect of NaF and DCV on adhesive curing kinetic, antibacterial activities against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Bacterial Flora of Human saliva (HSBF) were comprehensively evaluated. Then, the synergistic effects of NaF nanoparticles and DCV on adhesive performance were studied in terms of fluoride ion (F-) release, antibacterial activity, hydrophilicity, surface potential, cytotoxicity, and bonding strength. RESULTS: DCV monomer could polymerize with other adhesive monomers without influencing C = C double conversion rate, while the addition amount of DCV would affect the hydrophilicity and bonding strength of the cured adhesives. The cationic quaternary ammonium group could reduce the burst release of negative F- for the adhesive at a NaF/DCV ratio (1:1, 2%), hence achieving both non-contact and contact antibacterial activity in an extended term without causing cytotoxicity. CONCLUSION: Mixing NaF nanoparticles and DCV into the dental resin adhesive can slow down the initial burst release of F- and prolong the release-type antibacterial effect. The ionic interaction between F- and quaternary ammonium groups, as well as, the effect of DCV on adhesive hydrophilicity, simultaneously influence the release behavior of F-. Co-incorporation of quanternary ammonium and fluoride improves adhesive's antibacterial performance for dental application. CLINICAL SIGNIFICANCE: Incorporating both NaF nanoparticles and DCV into dental resin adhesive could provide an efficient strategy for dental restoration as well as the prevention of secondary caries.

Self-Sacrificially Degradable Pseudo-Semiconducting Polymer Nanoparticles that Integrate NIR-II Fluorescence Bioimaging, Photodynamic Immunotherapy, and Photo-Activated Chemotherapy.

Semiconducting polymers (SP) hold great promise for cancer phototherapy due to their excellent optical properties; however, their clinical application is still hampered by their poor biodegradability. Herein, a self-sacrificially biodegradable pseudo-semiconducting polymer (PSP) for NIR-II fluorescence bioimaging, photodynamic immunotherapy, and photoactivated chemotherapy (PACT) is reported. The PSP can further co-assemble with an amphiphilic polyester with pendant doxorubicin (DOX) in its side chains via reactive oxygen species (ROS)-responsive thioketal linkages (PEDOX ), which are denoted as NP@PEDOX /PSP. The NP@PEDOX /PSP can accumulate at tumor sites and generate ROS for photodynamic immunotherapy as well as near-infrared-II fluorescence (NIR-II) for bioimaging upon irradition at 808 nm. The ROS could break up thioketal linkages in PEDOX , resulting in rapid doxorubicin (DOX) release for PACT. Finally, both PEDOX and PSP are degraded sacrificially by intracellular glutathione (GSH), resulting in the dissociation of NP@PEDOX /PSP. This work highlights the application of self-sacrificially degradable PSP for NIR-II fluorescence bioimaging, photodynamic immunotherapy, and PACT in cancer therapy.

Dual-Cascade Responsive Nanoparticles Enhance Pancreatic Cancer Therapy by Eliminating Tumor-Resident Intracellular Bacteria.

The limited drug penetration and robust bacteria-mediated drug inactivation in pancreatic cancer result in the failure of chemotherapy. To fight against these issues, a dual-cascade responsive nanoparticle (sNP@G/IR) that can sequentially trigger deep penetration, killing of intratumor bacteria, and controlled release of chemo-drug, is reported. sNP@G/IR consists of a hyaluronic acid (HA) shell and glutathione (GSH)-responsive polymer-core (NP@G/IR), that encapsulates gemcitabine (Gem) and photothermal agent (IR1048). The polymer core, as an antibiotic alternative, is tailored to exert optimal antibacterial activity and selectivity. sNP@G/IR actively homes in on the tumor due to the CD44 targeting of the HA shell, which is subsequently degraded by the hyaluronidase in the extracellular matrix. The resultant NP@G/IR in decreased size and reversed charge facilitates deep tumor penetration. After cellular endocytosis, the exposed guanidine on NP@G/IR kills intracellular bacteria through disrupting cell membranes. Intracellular GSH further triggers the controlled release of the cargo. Thus, the protected Gem eventually induces cell apoptosis. Under laser irradiation, the hyperthermia of IR1048 helps further elimination of tumors and bacteria. Moreover, sNP@G/IR activates immune response, thereby reinforcing anticancer capacity. Therefore, this dual-cascade responsive sNP@G/IR eliminates tumor-resident intracellular bacteria and augments drug delivery efficacy, providing a new avenue for improving cancer therapy.

Bioinspired porous microspheres for sustained hypoxic exosomes release and vascularized bone regeneration.

Exosomes derived from mesenchymal stem cells (MSCs) have demonstrated regenerative potential for cell-free bone tissue engineering, nevertheless, certain challenges, including the confined therapeutic potency of exosomes and ineffective delivery method, are still persisted. Here, we confirmed that hypoxic precondition could induce enhanced secretion of exosomes from stem cells from human exfoliated deciduous teeth (SHEDs) via comprehensive proteomics analysis, and the corresponding hypoxic exosomes (H-Exo) exhibited superior potential in promoting cellular angiogenesis and osteogenesis via the significant up-regulation in focal adhesion, VEGF signaling pathway, and thyroid hormone synthesis. Then, we developed a platform technology enabling the effective delivery of hypoxic exosomes with sustained release kinetics to irregular-shaped bone defects via injection. This platform is based on a simple adsorbing technique, where exosomes are adsorbed onto the surface of injectable porous poly(lactide-co-glycolide) (PLGA) microspheres with bioinspired polydopamine (PDA) coating (PMS-PDA microspheres). The PMS-PDA microspheres could effectively adsorb exosomes, show sustained release of H-Exo for 21 days with high bioactivity, and induce vascularized bone regeneration in 5-mm rat calvarial defect. These findings indicate that the hypoxic precondition and PMS-PDA porous microsphere-based exosome delivery are efficient in inducing tissue regeneration, hence facilitating the clinical translation of exosome-based therapy.

Degradable Pseudo Conjugated Polymer Nanoparticles with NIR-II Photothermal Effect and Cationic Quaternary Phosphonium Structural Bacteriostasis for Anti-Infection Therapy.

Photothermal therapy based on conjugated polymers represents a promising antibacterial strategy but still possesses notable limitations. Herein, degradable pseudo conjugated polymers (PCPs) containing photothermal molecular backbones and reactive oxygen species (ROS)-sensitive thioketal bonds are designed. Triphenylphosphine (PPh3 ) is introduced into PCPs to generate phosphonium-based PCPs (pPCPs), which further assembled with hyaluronic acid into pPCP nanoparticles (pPCP-NPs). pPCP-NPs with quaternary phosphonium cations selectively anchor on and destroy bacterial cell membranes through electrostatic action. Under 1064 nm laser irradiation, pPCP-NPs (pPCP-NPs/+L) produce near-infrared-II (NIR-II) photothermal antibacterial effect, thereby killing bacteria in a sustained manner. pPCP-NPs are readily degraded upon ROS abundant at infection sites, therefore exhibiting enough biosafety. pPCP-NPs/+L display an almost 100% bacterial inhibition rate in vitro and resultin a nearly complete recovery of bacteria-induced mouse wounds. A further metabolomics analysis denotes that pPCP-NPs/+L work in a concerted way to induce bacterial DNA damage, inhibit bacterial carbon/nitrogen utilization and amino acid/nucleotide synthesis. Taken together, degradable pPCP-NPs with both NIR-II photothermal effect and cationic phosphonium structural bacteriostasis provide a new avenue for antibiotics-alternative anti-infection therapy.

Folate-modified triptolide liposomes target activated macrophages for safe rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial joint hyperplasia, joint inflammation, cartilage erosion and bone destruction. Macrophages play an essential role in the pathogenesis of RA, and folate receptor ß (FR-ß) is highly expressed on the surface of activated synovial macrophages in RA patients. Triptolide (TP) has anti-inflammatory properties, and it can protect the cartilage matrix, but its clinical application has been limited due to poor solubility, low bioavailability and systemic toxicity. Therefore, we constructed folate-modified triptolide liposomes (FA-TP-Lips) to target macrophages, thereby treating RA in a safe and effective way. The experiments indicated that FA-TP-Lips had properties of small particle size, uniform particle size distribution, high drug encapsulation and long circulation. Furthermore, FA-TP-Lips showed reduced cytotoxicity, increased cellular uptake and significant anti-inflammatory effects in vitro. It also inhibited osteoclastogenesis. In vivo experiments revealed that liposomes could prolong the circulation of TP in the body, as well as exhibit significant cartilage-protective and anti-inflammatory effects with lower toxicity compared with the free TP group, thereby providing a promising new approach for the treatment of RA.

Lysosome activable polymeric vorinostat encapsulating PD-L1KD for a combination of HDACi and immunotherapy.

PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to the exhaustion of T cells. Studies have shown that the epigenetic regulation drug histone deacetylase inhibitor (HDACi) may be able to reverse exhausted T cells by changing the epigenetic transcription program. Therefore, the combination of epigenetic therapy and PD-1/PD-L1 blockade therapy is expected to reverse the immune escape, whereas the overriding goal should aim at the spontaneous release and synergy of PD-1/PD-L1 blocking siRNA and HDACi. In this study, we develop PDDS{polyethylene glycol-b-asparaginate(diethylenetriamine-vorinostat), (PEG-b-P[Asp(DET-SAHA)n] PPDS)}encapsulating siRNA-PD-L1to provide micelles siRNA-PD-L1-loaded micelles (siRNA@PPDS). Transmission electron microscope (TEM) images demonstrate that siRNA@PPDS micelles presented spherical morphology with a size of about 120 nm; hydrodynamic data analysis indicates pH sensitivity of siRNA@PPDS micelles. The experiments reveal that siRNA@PPDS micelles could be well uptaken by the tumor cells to silence the expression of PD-L1 protein in a dose-dependent manner; compared with the free SAHA, the SAHA-loaded micelles PPDS show higher cytotoxicity to induce tumor cell apoptosis and block cell cycle in G1 phase on melanoma-bearing mice, siRNA@PPDS has shown outstanding inhibition of tumor growth and pulmonary metastasis. By comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth, recurrence, and metastasis in clinic.

A Near-Infrared-II Polymer with Tandem Fluorophores Demonstrates Superior Biodegradability for Simultaneous Drug Tracking and Treatment Efficacy Feedback.

NIR-II (1000-1700 nm) fluorescence imaging is continually attracting strong research interest. However, current NIR-II imaging materials are limited to small molecules with fast blood clearance and inorganic nanomaterials and organic conjugated polymers of poor biodegradability and low biocompatibility. Here, we report a highly biodegradable polyester carrying tandem NIR-II fluorophores as a promising alternative. The polymer encapsulated a platinum intercalator (56MESS, (5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)) and was conjugated with both a cell-targeting RGD peptide and a caspase-3 cleavable peptide probe to form nanoparticles for simultaneous NIR-II and apoptosis imaging. In vitro, the nanoparticles were approximately 4-1000- and 1.5-10-fold more potent than cisplatin and 56MESS, respectively. Moreover, in vivo, they significantly inhibited tumor growth on a multidrug-resistant patient-derived mouse model (PDXMDR). Finally, through label-free laser desorption-ionization mass spectrometry imaging (MALDI-MSI), in situ 56MESS release in the deeper tumors was observed. This work highlighted the use of biodegradable NIR-II polymers for monitoring drugs in vivo and therapeutic effect feedback in real-time.