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The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment., (© 2024 Wiley‐VCH GmbH.)

Anexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off-target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys (Nap-IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap-IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor-instructed nanoparticle-to-nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap-IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap-IR can be applied in clinical ovarian cancer therapy in the near future., (© 2024 Wiley‐VCH GmbH.)

Current molecular photoacoustic (PA) probes are designed with either stimulus-turned "on" or assembly-enhanced signals to trace biological analytes/events. PA probes based on the nature-derived click reaction between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) (i.e., CBT-Cys click reaction) possess both "turn-on" and "enhanced" PA signals; and thus, should have higher sensitivity. Nevertheless, such PA probes, particularly those for sensitive imaging of tumor hypoxia, remain scarce. Herein, a PA probe NI-Cys(StBu)-Dap(IR780)-CBT (NI-C-CBT) is rationally designed, which after being internalized by hypoxic tumor cells, is cleaved by nitroreductase under the reduction condition to yield cyclic dimer C-CBT-Dimer to turn the PA signal "ON" and subsequently assembled into nanoparticles C-CBT-NPs with additionally enhanced PA signal ("Enhanced"). NI-C-CBT exhibits 1.7-fold "ON" and 3.2-fold overall "Enhanced" PA signals in vitro. Moreover, it provides 1.9-fold and 2.8-fold overall enhanced PA signals for tumor hypoxia imaging in HeLa cells and HeLa tumor-bearing mice, respectively. This strategy is expected to be widely applied to design more "smart" PA probes for sensitive imaging of important biological events in vivo in near future., (© 2023 Wiley‐VCH GmbH.)

Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life-threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)-containing antibiotic-peptide precursor Ada-Gly-Tyr-Val-Ala-Asp-Cys(StBu)-Lys(Ciprofloxacin)-CBT (Cip-CBT-Ada), we propose a strategy of tandem guest-host-receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest-host recognition, Cip-CBT-Ada is decorated with a β-cyclodextrin-heptamannoside (CD-M) derivative to yield Cip-CBT-Ada/CD-M, which is able to target mannose receptor-overexpressing macrophages via multivalent ligand-receptor recognition. After uptake, Cip-CBT-Ada/CD-M undergoes caspase-1 (an overexpressed enzyme during S. aureus infection)-initiated CBT-Cys click reaction to self-assemble into ciprofloxacin nanoparticle Nano-Cip. In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip-CBT-Ada, Cip-CBT-Ada/CD-M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus-infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest-host-receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently., (© 2023 Wiley-VCH GmbH.)

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T 2 -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T 2 -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T 2 -weighted MRI studies using MDA-MB-231 murine xenografts show that the T 2 -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T 2 -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T 2 contrast agent for the clinical diagnosis of cancers at an early stage., (© 2023 Wiley-VCH GmbH.)

Staphylococcus aureus (S. aureus) remains a leading cause of bacterial infections. However, eradication of S. aureus infections with common antibiotics is increasingly difficult due to outbreaks of drug resistance. Therefore, new antibiotic classes and antibacterial strategies are urgently in demand. Herein, it is shown that an adamantane-peptide conjugate, upon dephosphorylation by alkaline phosphatase (ALP) constitutively expressed on S. aureus, generates fibrous assemblies in situ to combat S. aureus infection. By attaching adamantane to a phosphorylated tetrapeptide Nap-Phe-Phe-Lys-Tyr(H 2 PO 3 )-OH, the rationally designed adamantane-peptide conjugate Nap-Phe-Phe-Lys(Ada)-Tyr(H 2 PO 3 )-OH (Nap-FYp-Ada) is obtained. Upon bacterial ALP activation, Nap-FYp-Ada is dephosphorylated and self-assembles into nanofibers on the surface of S. aureus. As revealed by cell assays, the assemblies of adamantane-peptide conjugates interact with cell lipid membrane and thereby disrupt membrane integrity to kill S. aureus. Animal experiments further demonstrate the excellent potential of Nap-FYp-Ada in the treatment of S. aureus infection in vivo. This work provides an alternative approach to design antimicrobial agents., (© 2023 Wiley-VCH GmbH.)

Chemotherapy has remained an effective and predominant cancer treatment for the past decades, but is hampered by its low response rate and severe systemic toxicity. Combination chemotherapies are proposed to address these issues, yet their therapeutic outcomes are still far from satisfactory. Thus, it is urgent to develop novel strategies to promote tumor chemosensitivity while reducing toxic side effects of chemotherapeutics. Herein, employing a rationally designed peptide conjugate Nap-Phe-Phe-Lys(SA-AZD8055)-Tyr(H 2 PO 3 )-OH (Nap-AZD-Yp), a novel approach of simultaneous intracellular nanofiber formation and autophagy inducer release is proposed for selectively sensitizing tumor to chemotherapy. Upon sequential catalyses of alkaline phosphatase and carboxylesterase, Nap-AZD-Yp undergoes nanosphere-to-nanofiber transition accompanied by autophagy inducer AZD8055 release in cancer cells. Cell experiments show enhanced endocytosis of anticancer drug doxorubicin and inhibition of cell migration due to the intracellular nanofiber formation. The released AZD8055 further activates excessive autophagy of cancer cells, sensitizing them to chemotherapy. Animal experiment results suggest Nap-AZD-Yp can significantly enhance the therapeutic effects of doxorubicin on tumors while mitigate its toxic adverse effects on normal tissues. It is anticipated that the "smart" concept in this work c be widely employed to develop novel combinational therapies for the treatment of cancers and other diseases in near future., (© 2022 Wiley-VCH GmbH.)

Salt-inducible kinase 2 (SIK2) is a promising target for ovarian cancer therapy due to its critical role in tumorigenesis and progression. Currently available SIK2 inhibitors have shown remarkable therapeutic effects on ovarian cancers in preclinical studies. However, direct administration of the SIK2 inhibitors may bring significant off-target effect, limiting their clinical applications. In this work, by rational design of a hydrogelator Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser-Ser-Ser-Asn-Leu-OH (Nap-S) to coassemble a SIK2 inhibitor HG-9-91-01 (HG), a SIK2-responsive supramolecular hydrogel (Gel Nap-S+HG) for local administration and SIK2-responsive release of HG is reported to efficiently suppress ovarian cancer metastasis. Under the activation of SIK2 overexpressed in ovarian cancers, Nap-S in the hydrogel is phosphorylated to yield hydrophilic Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser(H 2 PO 3 )-Ser-Ser-Asn-Leu (Nap-Sp), triggering the disassembly of the hydrogel and a responsive release of the inhibitor. Cell experiments indicate that sustained release of HG from Gel Nap-S+HG induce a prominent therapeutic effect on cancer cells by inhibiting SIK2 and phosphorylation of their downstream signaling molecules. Animal experiments demonstrate that, compared with those tumor model mice treated with free HG, Gel Nap-S+HG-treatment mice show an enhanced inhibition on ovarian tumor growth and metastasis. It is anticipated that the Gel Nap-S+HG can be applied for ovarian cancer therapy in clinic in the near future., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Direct, noninvasive, and real-time imaging of Staphylococcus aureus (S. aureus) infection is of great value for quick diagnosis of related disease in clinic, but remains challenging. Herein, employing a rationally designed near-infrared fluorescence probe Cys(StB u)-EDA-Thioketal-Lys(Cy5.5)-CBT (TK-CBT) and a CBT-Cys click reaction, the fluorescence-quenched nanoparticles TK-CBT-NPs are facilely prepared. Upon oxidation by the abundant reactive oxygen species in S. aureus-infected macrophages, TK-CBT-NPs are fractured, turning the fluorescence "on" for imaging infections in vitro and in vivo. Specifically, TK-CBT-NPs show a 6.1-fold fluorescence imaging signal enhancement of the macrophages that are infected by S. aureus for 20 h in vitro. At 4 h postinjection, TK-CBT-NPs show a 2.8-fold fluorescence imaging signal enhancement of the sites in mice that are infected by S. aureus for 24 h. It is anticipated that TK-CBT-NPs could be applied for diagnosis of S. aureus infections in clinic in the near future., (© 2022 Wiley-VCH GmbH.)

Cathepsin B (CTSB) is a lysosomal protease that is overexpressed in the early stage of many cancer types. Precise evaluation of CTSB expression in vivo may provide a promising method for the early diagnosis of cancers. By virtue of the high-resolution PA imaging modality, a "smart" photoacoustic (PA) probe Cypate-CBT, which can self-assemble to cypate-containing nanoparticles in response to abundant GSH and CTSB inside tumor cells, was developed for the sensitive and specific detection of CTSB activity. Compared with unmodified Cypate, our probe Cypate-CBT exhibited a 4.9-fold or 4.7-fold PA signal enhancement in CTSB-overexpressing MDA-MB-231 cancer cells or tumors, respectively, revealing intracellular accumulation of the probe after CTSB-initiated self-assembly. We expect Cypate-CBT to be employed as an effective PA imaging agent for clinical diagnosis of cancer at early stages., (© 2021 Wiley-VCH GmbH.)

Selectively inducing lysosomal membrane permeabilization (LMP) is a promising strategy for cancer therapy. But integrating alkaline phosphatase (ALP)-instructed self-assembly and lysosome-targeting to induce LMP for selective killing of cancer cells was not reported. Herein, a pyrene-peptide conjugate Py-Phe-Phe-Glu-Tyr(H 2 PO 3 )-Gly-lyso (Py-Yp-Lyso) is rationally designed and demonstrated for its lysosome-targeting cytotoxicity on cancer cells, together with its pyrene (Py) excimer fluorescence turning "on" at 480 nm. In vitro results showed that, Py-Yp-Lyso is efficiently dephosphorylated by ALP to yield Py-Phe-Phe-Glu-Tyr-Gly-lyso (Py-Y-Lyso) which self-assembles into nanofibers. Cell experiments verified that, after being taken up by HeLa cells, the excimer fluorescence of Py-Yp-Lyso assemblies has turned "on" and the assemblies specifically target the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py-Yp-Lyso has the highest inhibition effect on HeLa tumors among the four compounds studied. This is anticipated for applying Py-Yp-Lyso to treat cancers in the clinic in the future., (© 2021 Wiley-VCH GmbH.)

The presence of bacteria in the tumor can cause cancer resistance to chemotherapeutics. To fight against bacterium-induced drug resistance, herein we design self-traceable nanoreservoirs that are simultaneously loaded with gemcitabine (an anticancer drug) and ciprofloxacin (an antibiotic) and are decorated with hyaluronic acid for active tumor targeting. The nanoreservoirs have a pH-sensitive gate and an enzyme-responsive gate that can be opened in the acidic and hyaluronidase-abundant tumor microenvironment to control drug release rates. Moreover, the nanoreservoirs can specifically target the tumor regions without eliciting evident toxicity to normal tissues, kill the intratumoral bacteria, and inhibit the tumor growth even in the presence of the bacteria. Unexpectedly, the nanoreservoirs can activate T cell-mediated immune responses through promoting antigen-presenting dendritic cell maturation and depleting immunosuppressive myeloid-derived suppressor cells in bacterium-infected tumors., (© 2021 Wiley-VCH GmbH.)

Intracellular self-assembly (ISA) is a versatile and powerful strategy for in situ constructing sophisticated and functional supramolecular nanostructures, which has been widely applied in biomedicine and biomedical engineering. Among the common building blocks for ISA, peptides have attracted increasingly attention due to their intrinsic bioactivity, biocompatibility, and biodegradability. Particularly, by conjugating functional motifs (e.g., probes or drugs) to peptides to yield the peptide conjugates, the latter show enhanced stability and efficiency, and probably new functions. In recent years, employing ISA of peptide conjugates for tumor imaging and treatment has achieved great progresses. Therefore, the recent progress of ISA of peptide conjugates is summarized in this progress report. Moreover, several examples of ISA of peptide conjugates for other important imaging or therapeutic applications are also introduced. Finally, a brief perspective on remaining challenges and potential directions for future research in this area is presented., (© 2020 Wiley-VCH GmbH.)

Transplant rejection is the key problem in organ transplantation and, in clinic, immunosuppressive agents such as tacrolimus are directly administered to the recipients after surgery for T-cell inhibition. However, direct administration of tacrolimus may bring severe side effects to the recipients. Herein, by rational design of two hydrogelators NapPhePheGluTyrOH (1) and Nap d-Phe dPheGluTyrOH (2), a facile method of immune responsive release of tacrolimus is developed from their hydrogels to overcome organ transplantation rejection. Upon incubation with protein tyrosine kinase, which is activated in T cells after organ transplantation, the tacrolimus-encapsulating Gel 1 or Gel 2 is disassembled to release tacrolimus. Cell experiments show that both Gel 1 and Gel 2 have better inhibition effect on the activated T cells than free drug tacrolimus. Liver transplantation experiments indicate that, after 7 days of treatment of same dose tacrolimus, the recipient rats in the Gel 2 group show significantly extended median survival time of 22 days while the recipients treated with conventional tacrolimus medication have a median survival time of 13 days. It is expected herein that this "smart" facile method of immune responsive release of tacrolimus can be applied to overcome organ transplantation rejection in clinic in the near future., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hydrogels consisting of carboxylic acid groups and N-isopropylacrylamide as pendants on their polymeric network usually exhibit volume expansion upon deprotonation or volume contraction when being heated. Demonstrated here is an anti-intuitive case of a hydrogel containing multiple carboxylic acid groups at each crosslinking point in the polymeric network, which shrinks upon increasing pH from 1 to 7 at 37 °C or expands upon heating from 25 to 37 °C at pH 1. The unexpected volume change originates from the high percentage of the crosslinker in the polymers, as detected by solid-state 13 C NMR spectroscopy. In addition, the volume changes are thermally reversible. As the first example of the use of functional hyper-crosslinkers to control the pH and thermal responses of nanogels, this work illustrates a new way to design soft materials with unusual behaviors., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Multidrug resistance (MDR) remains the biggest challenge in treating cancers. Herein we propose the intracellular self-assembly of nanodrugs as a new strategy for overcoming MDR. By employing a biocompatible condensation reaction, we rationally designed a taxol derivative Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys(taxol)-2-cyanobenzothiazole (CBT-Taxol) which could be subjected to furin-controlled condensation and self-assembly of taxol nanoparticles (Taxol-NPs). In vitro and in vivo studies indicated that, compared with taxol, CBT-Taxol showed a 4.5-fold or 1.5-fold increase in anti-MDR effects, respectively, on taxol-resistant HCT 116 cancer cells or tumors without being toxic to the cells or the mice. Our results demonstrate that structuring protease-susceptible agents and assembling them intracellularly into nanodrugs could be a new optimal strategy for overcoming MDR., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polymer hydrogels and small-molecule-based (SMB) supramolecular hydrogels have been widely explored. But oligomeric hydrogels have remained a challenge because synthetic difficulties of the oligomers and control of their amphiphilicities. Reported herein is the rational design of two precursors Cys(SEt)-Lys-CBT (1) and (Cys-Lys-CBT)2 (2) (CBT=2-cyano-6-aminobenzothiazole) and the use of a biocompatible condensation to prepare oligomeric hydrogels. Glutathione reduction of 1 or 2 yields the same gelator Cys-Lys-CBT (3) which condenses with each other to yield amphiphilic cyclic oligomers. The oligomers instantly self-assemble into nanofibers and form oligomeric hydrogels with similar mechanic properties. Chemical analyses indicated that the major condensation product in both two hydrogels is a cyclic dimer. Considering its biocompatibility, optimal mechanical strength, and biodegradability, we believe that our oligomeric hydrogel might be useful for long-term drug delivery in the future., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fragrant nitrogen-doped carbon dots of gram scale can be prepared from commercial bee pollens by a hydrothermal process. These carbon dots of 1-2 nm in size show promising applications in cellular imaging and catalysis/photocatalysis.