Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion.

Shigella is a Gram-negative bacterium that causes bacillary dysentery worldwide. It invades the intestinal epithelium to elicit intense inflammation and tissue damage, yet the underlying mechanisms of its host selectivity and low infectious inoculum remain perplexing. Here, we report that Shigella co-opts human α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, to enhance its adhesion to and invasion of mucosal tissues. HD5 promoted Shigella infection in vitro in a structure-dependent manner. Shigella, commonly devoid of an effective host-adhesion apparatus, preferentially targeted HD5 to augment its ability to colonize the intestinal epithelium through interactions with multiple bacterial membrane proteins. HD5 exacerbated infectivity and Shigella-induced pathology in a culture of human colorectal tissues and three animal models. Our findings illuminate how Shigella exploits innate immunity by turning HD5 into a virulence factor for infection, unveiling a mechanism of action for this highly proficient human pathogen.

Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance.

Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.

Rebooting the Adaptive Immune Response in Immunotherapy-Resistant Lung Adenocarcinoma Using a Supramolecular Albumin.

Despite the availability of immune checkpoint inhibitors (ICBs) significantly prolonging the life expectancy of some lung adenocarcinoma (LUAD) patients, their implementation and long-term effectiveness are hampered by the growing issue of acquired resistance. Herein, the bioinformatics analysis of immunotherapy-resistant LUAD patients and the system analysis of Anti-PD1-resistant mice models once again validate that the resistance-associated Wnt/ß-catenin pathway offers a promising avenue for ICB sensitization. Consequently, a mild and convenient self-assembly between albumin and carnosic acid (CA), a Wnt inhibitor is employed, to develop a supramolecular albumin known as ABCA, serving as a reactivator for ICB. As anticipated, ABCA effectively suppress the Wnt/ß-catenin cascade in vitro and leads to significant inhibition of cell proliferation while promoting apoptosis. Most notably, ABCA restores the anticancer efficacy of Anti-PD1 in immunotherapy-resistant LUAD orthotopic allografting mice models by reinvigorating the adaptive immune response mediated by T lymphocytes. Furthermore, ABCA exhibits minimal adverse effects during treatment and high-dose toxicity tests, underscoring its excellent potential for clinical translation. Collectively, the present work possesses the potential to provide innovative perspectives on the advancement of optimized immunotherapies targeting drug resistance, while also presenting a promising avenue for translating Wnt inhibitors into immunotherapeutic drugs for their clinical application.

A Tumor-Targeting Metal-Organic Nanoparticle Constructed by Dynamic Combinatorial Chemistry toward Accurately Redressing Carcinogenic Wnt Cascade.

Targeted and immunological therapy have revolutionized the malignancy treatment, but is suffering from the dose-limiting side effects and inadequate responsiveness. The emerging nanoscale infinite coordination polymers provide a feasible strategy for tumor targeting and immune sensitization. Herein, a "one-pot" self-assembled strategy based on dynamic combinatorial chemistry (DCC) principle is designed to construct a tumor-targeting metal-organic nanoparticle (MOICP) through a spontaneous co-assembling among three metal-organic coordination polymers tuned by a Wnt-inhibitor carnosic acid (CA). Responding to the tumor microenvironment, MOICP presents an optimized tumor-preferential accumulation and the satisfactory biosafety. MOICP is more active in vitro and in vivo than CA in suppressing of Wnt signaling pathway, and potently inhibits tumor growth in a patient-derived xenograft model of Wnt-activated pancreatic carcinoma. Moreover, MOICP reverses the lack of intratumoral infiltration of T lymphocytes, and hence augments the action of Anti-PD1 (programmed cell death protein 1) immunotherapy in B16F10 melanoma allograft mice model. This clinically viable MOICP can not only be applied to Wnt inhibition for cancer targeted therapy and immunotherapeutic sensitization, but also provides a de novo pattern for nanomedicine architecture with cargo-initiated co-self-assembly guided by DCC, thereby bringing new inspiration in general for disease intervention.

Turing miRNA into infinite coordination supermolecule: a general and enabling nanoengineering strategy for resurrecting nuclear acid therapeutics.

BACKGROUND: Clinical translation of therapeutic nuclear acid, particularly those targeting tumor progression, has been hampered by the intrinsic weaknesses of nuclear acid therapeutic including poor systemic stability, rapid clearance, low membrane permeability and lack of targeting ability. Small nuclear acid engineered into carrier-free nanodrugs with structural stability and disease targeting may be viable to overcome pharmaceutical obstacles of nuclear acid. METHODS: A general method through a mild and simple chemistry was established to convert therapeutic miRNA into an infinite Auric-sulfhydryl coordination supramolecular miRNA termed IacsRNA with near-spherical nanostructure, high colloid as well as anti-hydrolysis stability and low macrophage uptakes. RESULTS: IacsRNA presented the increased half-life period in circulation and accumulation at tumor sites in comparison to normal miRNA. Moreover, Iacs-miR-30c showed no toxicity of viscera and sanguis system in the 5-time injection dosage of the treatment. More importantly, Iacs-miR-30c potently suppressed the Wnt signaling pathway in vitro and in vivo, and effectively sensitized both potency of 5-Fu in PDX model of colon cancer and Anti-PD1 in B16F10 homograft model of melanoma. CONCLUSION: Collectively, this work amply confirmed the design of IacsRNA as a general and viable strategy of nano-pharmaceutic to concert flimsy therapeutic miRNA into potential drugs. Considering from a broader perspective, the miRNA-initiated infinite coordination self-assembly strategy has distinct advantages in resurrecting nuclear acid therapeutics, probably bringing new inspiration to RNA-derived therapeutics of a great variety of human diseases including cancer.

A Bionic Nano-Band-Aid Constructed by the Three-Stage Self-Assembly of Peptides for Rapid Liver Hemostasis.

Critical challenges remain in trauma emergency and surgical procedures involving liver bleeding, particularly in perforating wounds that cannot be pressed and large wounds that cannot be sewn. Self-assembling peptide hydrogels are particularly attractive due to their intrinsic biocompatibility and programmability. Herein, we develop a nano-band-aid (NBA) through a three-stage self-assembly strategy of two functionalized peptides, which were first coassembled into nanofibers and then woven to a meshlike network driven by Ca2+. Then, catalyzed by blood coagulation factor XIIIa (FXIIIa), NBA underwent a third stage, self-assembly into a densely compacted physical barrier to stop and control the bleeding. As expected, NBA rapidly and efficiently stopped the bleeding in rat liver scratches while effectively reducing the inflammation around the wound and promoting the wound healing. This bionic self-assembly strategy will provide a clinically potential peptide-based treatment for fatal liver bleeding and reinvigorate efforts to develop self-assembling peptide hydrogels as hemostatic agents.

De Novo Nano-Erythrocyte Structurally Braced by Biomimetic Au(I)-peptide Skeleton for MDM2/MDMX Predation toward Augmented Pulmonary Adenocarcinoma Immunotherapy.

In nature, cells rely on a structural framework called the "cytoskeleton" to maintain their shape and polarity. Based on this, herein a new class of cell-mimicking nanomedicine using bionic skeletons constituted by the oligomeric Au(I)-peptide complex is developed. The peptide function of degrading pathological MDM2 and MDMX is used to synthesize an oligomeric Au(I)-PMIV precursor capable of self-assembling into a clustered spherical bionic skeleton. Through coating by erythrocyte membrane, an erythrocyte-mimicking nano-cell (Nery-PMIV) is developed with depressed macrophage uptakes, increased colloidal stability, and prolonged blood circulation. Nery-PMIV potently restores p53 and p73 in vitro and in vivo by degrading MDM2/MDMX. More importantly, Nery-PMIV effectively augments antitumor immunity elicited by anti-PD1 therapy in a murine orthotopic allograft model for LUAD and a humanized patient-derived xenograft (PDX) mouse model for LUAD, while maintaining a favorable safety profile. Taken together, this work not only presents evidence showing that MDM2/MDMX degradation is a potentially viable therapeutic paradigm to synergize anti-PD1 immunotherapy toward LUAD carrying wild-type p53; it also suggests that cell-mimicking nanoparticles with applicable bionic skeletons hold tremendous promise in offering new therapies to revolutionize nanomedicine in the treatment of a myriad of human diseases.

Chiral Protein Supraparticles for Tumor Suppression and Synergistic Immunotherapy: An Enabling Strategy for Bioactive Supramolecular Chirality Construction.

The design of bioactive supramolecular chirality is always hampered by the lack of feasible schemes to assigned specific biological activities. Herein, we developed a "mirror-image peptide grafting" method to graft the epitopes of bioactive d-peptide onto the miniprotein template to construct a self-assembled supraparticle. Grafting DPMIß, a 12-mer d-enantiomeric peptide functioned as the p53 agonist, onto Apamin, we successfully constructed a self-assembled d-enantiomeric miniprotein supermolecule nanoparticle, termed DMSN. This chiral supraparticle possesses a favorable pharmaceutical profile including the passive tumor targeting, cell membrane penetration, intracellular reductive responsiveness, and endosome escaping. DMSN showed in vitro and in vivo p53-dependent antiproliferative activity and augmented antitumor immunity elicited by anti-PD1 therapy. This enabling strategy will allow us to fabricate a class of peptide/protein-derived supramolecular chirality with predictable biological activities and will likely have a broad impact on the chiral nanotechnology at the service of prevention and treatment of human diseases.

Targeted disruption of the BCL9/ß-catenin interaction by endosomal-escapable nanoparticles functionalized with an E-cadherin-derived peptide.

Abnormal activation of the Wnt/ß-catenin signaling pathway, which underlies multiple malignancies, promotes tumor progression; drugs that can block this pathway are therefore highly attractive candidates for anticancer therapy. Using a therapeutic peptide derived from E-cadherin region V (cECRV), we sought to develop a potent and selective antagonist of ß-catenin that can disrupt the carcinogenic interaction between ß-catenin and BCL9. More importantly, to overcome the pharmacological obstacles of peptide-derived therapeutics (poor nuclease stability and low membrane permeability), a gold nanoparticle (AuNP)-based nanocarrier was designed to deliver cECRV into the cytoplasm to modulate the intracellular interaction of ß-catenin and BCL9. The resultant nanoparticle, pAuNP-cECRV, showed no cytotoxicity towards normal peripheral blood mononuclear cells and induced cycle arrest and subsequent apoptosis of Wnt-hyperactive cancer cells by antagonizing ß-catenin to inhibit the Wnt pathway. Our results indicate that pAuNP-cECRV is very promising for application as an efficient and safe peptide delivery vector for cancer therapy.

Biomimetic and Self-Assembled Nanoclusters Targeting ß-Catenin for Potent Anticancer Therapy and Enhanced Immunotherapy.

Immune checkpoint blockade therapies fail to induce immune response in the vast majority of cancer patients, so developing robust adjuvants for increasing tumor immune response is central for effective tumor immunotherapy. The Wnt/ß-catenin pathway is a crucial oncogenic signal in relation to tumor immune evasion; however, none of the Wnt inhibitor under clinical or preclinical phases has demonstrated satisfactory specificity. Thus, new compounds or modalities that tumor specifically modulate the Wnt signal will be of great significance and value in clinical tumor immunotherapy. Herein, inspired by a natural phenomenon in cancer cells that the Achilles' Heel of oncoprotein ß-catenin, H1 helix, predisposes ß-catenin to oligomerization for proteasomal degradation and can be exacerbated by carnosic acid (CA, a Wnt inhibitor), we developed a size-tuned nanocluster (CAcluster) with well-defined supramolecular nanostructure by coassembling CA and H1 peptide. With the inherent enhanced permeability and retention (EPR) effect and the designed tumor microenvironment (TME) responsiveness, the CAcluster tumor specifically suppress the Wnt/ß-catenin cascade in vivo, while maintaining a highly favorable biosafety profile. More importantly, the CAclusterin vivo improved the tumor response to the PD1/PD-L1 immune checkpoint blockade in melanoma and colon cancer. This study provides new insights into the biomimetic coassembly strategy to design supramolecular nanostructured adjuvants for hazard-free Wnt suppression and synergy with tumor immunotherapy.

A Hierarchical Peptide-Lanthanide Framework To Accurately Redress Intracellular Carcinogenic Protein-Protein Interaction.

Intracellular protein-protein interactions (PPIs) are a vital and yet underexploited class of therapeutic targets for their crucial roles in cellular processes and involvement in disease initiation and progression. Although some successful chemistry and nanotechnologies have been introduced into peptide PPI modulators to allow cell and tissue permeability, significant challenges remain with regard to the efficient and precise modulation of PPIs within specific cells of diseased tissues, such as solid tumors. Herein, an intratumoral transformable hierarchical framework, termed iPLF, was fabricated via a two-step self-assembly between peptides and lanthanide-doped nanocrystals. In this proof-of-concept study, using NanoEL effect, TME response, and tumor marker targeting, iPLF in vivo delivered the p53-MDM2 modulator DPMI into tumor cells and ß-catenin-Bcl9 modulator Bcl9p into tumor stem cells. This crafted programmed nanomedicine with triple-stage delivery and responsiveness accurately modulated the specific intracellular protein-protein interactions, resulting in the suppression of tumor growth and metastasis in vivo, while maintaining a highly favorable safety profile. iPLF reached the goal of accurate, potent, and hazard-free intracellular PPI modulation, thereby providing a means to improve current knowledge of PPI networks and a novel therapeutic strategy for a great variety of diseases.

Self-Assembly of Therapeutic Peptide into Stimuli-Responsive Clustered Nanohybrids for Cancer-Targeted Therapy.

Clinical translation of therapeutic peptides, particularly those targeting intracellular protein-protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide-Au nanohybrid, followed by further self-assembling into higher-order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed ß-catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/ß-catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD-L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide-derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis.

Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.

Reversing MET-Mediated Resistance in Oncogene-Driven NSCLC by MET-Activated Wnt Condensative Prodrug.

The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/ß-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/ß-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by ß-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/ß-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.

A Transdermal Prion-Bionics Supermolecule as a RAB3A Antagonist for Enhancing Facial Youthfulness.

The mechanism research of skin wrinkles, conducted on volunteers underwent high-intensity desk work and mice subjected to partial sleep deprivation, revealed a significant reduction in dermal thickness associated with the presence of wrinkles. This can be attributed to the activation of facial nerves in a state of hysteria due to an abnormally elevated interaction between SNAP25 and RAB3A proteins involved in the synaptic vesicle cycle (SVC). Facilitated by AI-assisted structural design, a refined peptide called RSIpep is developed to modulate this interaction and normalize SVC. Drawing inspiration from prions, which possess the ability to protect themselves against proteolysis and invade neighboring nerve cells through macropinocytosis, RSIpep is engineered to demonstrate a GSH-responsive reversible self-assembly into a prion-like supermolecule (RSIprion). RSIprion showcases protease resistance, micropinocytosis-dependent cellular internalization, and low adhesion with constituent molecules in the cuticle, thereby endowing it with the transdermic absorption and subsequent biofunction in redressing the frenzied SVC. As a facial mud mask, it effectively reduces periorbital and perinasal wrinkles in the human face. Collectively, RSIprion not only presents a clinical potential as an anti-wrinkle prion-like supermolecule, but also exemplifies a reproducible instance of bionic strategy-guided drug development that bestows transdermal ability upon the pharmaceutical molecule.

Reinvigoration of cytotoxic T lymphocytes in microsatellite instability-high colon adenocarcinoma through lysosomal degradation of PD-L1.

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP ß, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP ß effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy.

Transforming Albumin into a Trojan Horse of Immunotherapy-Resistant Colorectal Cancer with a High Microsatellite Instability.

The therapeutic response of microsatellite instability-high (MSI-H) colorectal cancer (CRC) to immune checkpoint inhibitors (ICI) is indeed surprising; however, the emergence of acquired resistance poses an even greater threat to the survival of these patients. Herein, bioinformatics analysis of MSI-H CRC samples revealed that Wnt signaling pathway represents a promising target for acquired immune reactivation, while subsequent analysis and biochemical testing substantiated the inclination of Wnt-hyperactive CRC cells to engage in macropinocytosis with human serum albumin (HSA). These findings have inspired us to develop an engineered HSA that not only possesses the ability to specifically target cancer cells but also effectively suppresses the Wnt/ß-catenin cascade within these malignant cells. In pursuit of this objective, a comprehensive screening of reported Wnt small-molecule inhibitors was conducted to evaluate their affinity with HSA, and it was discovered that Carnosic acid (CA) exhibited the highest affinity while simultaneously revealing multiple binding sites. Further investigation revealed that CA HSA the capability to engineer HSA into spherical and size-tunable nanostructures known as eHSA (Engineering HSA particle), which demonstrated optimized macropinocytosis-dependent cellular internalization. As anticipated, eHSA effectively suppressed the Wnt signaling pathway and reactivated the acquired immune response in vivo. Furthermore, eHSA successfully restored sensitivity to Anti-PD1's anticancer effects in both subcutaneous and orthotopic mouse homograft models of MSI-H CRC, as well as a humanized hu-PBMC patient-derived orthotopic xenograft (PDOX) mouse model of MSI-H CRC, all while maintaining a favorable safety profile. The collective implementation of this clinically viable immune reactivation strategy not only enables the delivery of Wnt inhibitors for CRC therapy, but also serves as an exemplary demonstration of precision-medicine-guided nanopharmaceutical development that effectively harnesses specific cellular indications in pathological states.

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis.

The coexistence of lung adenocarcinoma (LUAD) with idiopathic pulmonary fibrosis (IPF), which has been extensively documented as a prominent risk factor for checkpoint inhibitor-related pneumonitis (CIP) in patients undergoing immunotherapy, has long been considered a restricted domain for the use of immune checkpoint inhibitors (ICIs). To overcome it, an approach was employed herein to specifically target PD-L1 within the cellular interior, surpassing the conventional focus solely on the cytomembrane, thereby facilitating the development of ICIs capable of distinguishing between LUAD cells and noncancerous cells based on their distinctive endocytic propensities. By exploiting the aurophilicity-driven self-assembly of a PD-L1 binding peptide (PDBP) and subsequently encapsulating it within erythrocyte membranes (EM), the resulting biomimetic ICIs protein EMS-PDBP exhibited extraordinary selectivity in internalizing LUAD cells, effectively targeting PD-L1 within cancer cells while hindering its membrane translocation. The EMS-PDBP treatment not only reactivated the antitumor immune response in the LUAD orthotopic allograft mouse model but also demonstrated a favorable safety profile by effectively eliminating any immune-related adverse events (irAEs). Most significantly, EMS-PDBP successfully and safely restored the antitumor immune response in a mouse model of LUAD with coexistent IPF, thus shattering the confines of ICIs immunotherapy. The reported EMS-PDBP collectively offers a potential strategy for immune reactivation to overcome the limitations of immunotherapy in LUAD coexisting with IPF.

Sealing the Pandora's vase of pancreatic fistula through entrapping the digestive enzymes within a dextrorotary (D)-peptide hydrogel.

A variety of therapeutic possibilities have emerged for skillfully regulating protein function or conformation through intermolecular interaction modulation to rectify abnormal biochemical reactions in diseases. Herein, a devised strategy of enzyme coordinators has been employed to alleviate postoperative pancreatic fistula (POPF), which is characterized by the leakage of digestive enzymes including trypsin, chymotrypsin, and lipase. The development of a dextrorotary (D)-peptide supramolecular gel (CP-CNDS) under this notion showcases its propensity for forming gels driven by intermolecular interaction. Upon POPF, CP-CNDS not only captures enzymes from solution into hydrogel, but also effectively entraps them within the internal gel, preventing their exchange with counterparts in the external milieu. As a result, CP-CNDS completely suppresses the activity of digestive enzymes, effectively alleviating POPF. Remarkably, rats with POPF treated with CP-CNDS not only survived but also made a recovery within a mere 3-day period, while mock-treated POPF rats had a survival rate of less than 5 days when experiencing postoperative pancreatic fistula, leak or abscess. Collectively, the reported CP-CNDS provides promising avenues for preventing and treating POPF, while exemplifying precision medicine-guided regulation of protein activity that effectively targets specific pathogenic molecules across multiple diseases.

Hydrogelation of peptides and carnosic acid as regulators of adaptive immunity against postoperative recurrence of cutaneous melanoma.

The in-situ activation of adaptive immunity at the surgical site has demonstrated remarkable efficacy in inhibiting various forms of tumour recurrence and even holds the promise of a potential cure. However, extensive research and bioinformatic analysis conducted in this study have unveiled the formidable challenge posed by melanoma-intrinsic ß-catenin signaling, which hinders the infiltration of cytotoxic T-lymphocytes (CTLs) and their subsequent anti-tumour action. To overcome this obstacle, a ß-catenin antagonist called carnosic acid (CA) was co-assembled with a RADA-rich peptide to create a nanonet-derived hydrogel known as Supra-gelδCA. This injectable hydrogel is designed to be retained at the surgical site while simultaneously promoting hemostasis. Importantly, Supra-gelδCA directly releases CA to the site of residual tumour lesions, thereby enhancing infiltration of CTLs and subsequently activating adaptive immunity. Consequently, it effectively suppresses postoperative recurrence of skin cutaneous melanoma (SKCM) in vivo. Collectively, the presented Supra-gelδCA not only provides an efficacious immunotherapy strategy for regulating adaptive immunity by overcoming the obstacle posed by melanoma-intrinsic ß-catenin signaling-induced absence of CTLs but also offers a clinically translatable hydrogel that revolutionizes post-surgical management of SKCM.