Sepsis is a critical global health challenge, characterized by dysregulated host responses and high mortality rates. Current treatment therapies inadequately address persistent immunoparalysis and adverse reactions, leaving survivors susceptible to recurrent infections. Herein, we developed the first β-glucan (BG) delivery system using self-assembling peptide hydrogels to combat immuneparalysis associated with sepsis. This hydrogel combines oxidized BG (BGA) and tuftsin-functionalized self-assembling peptides (t-RADA16) to create an injectable glycopeptide hydrogel (BGA@t-RADA16). Upon subcutaneous injection, the hydrogel forms a dual-functional platform consisting of a “sustained-release depot” of BGA and a local “trained immunity center”, where the three-dimensional network of peptide nanofibers actively recruits macrophages and the BGA educates them in-situ. This endows the macrophages with an immune memory function, generating a rapid and powerful defense against secondary infection, and forming a “targeted-sustained-response” cascade treatment system. The results demonstrate that the glycopeptide hydrogel reduces organ damage, lowers sepsis mortality and confers protection against secondary infections by coordinating the activation of both innate and adaptive immune pathways. Furthermore, BGA-P@t-RADA16 simultaneously clears acute-phase pathogens and provides long-term immune training by loading polymyxin B within a single system, which truly addresses the problem of “immune imbalance” in the pathological process of sepsis. BGA@t-RADA16 provides a new tool for sepsis immunotherapy, pioneering an integrated strategy of “immune training, acute intervention and long-term defense”. This strategy is expected to be an important breakthrough in the treatment of sepsis and related immune disorders.

Immunotherapy has revolutionized lung cancer treatment; however, response rates remain suboptimal. Alveolar macrophages (AMs) within the tumor microenvironment contribute to immunotherapy resistance by inhibiting T cell function through metabolic exhaustion, as well by promoting tumor progression via a pro-tumor M2-like phenotype. Here, we describe a precision-engineered, cascade-targeted liposomal nanomedicine (pCAR-P3/LNP) that enables in situ reprogramming of AMs via a multi-step targeting strategy-including lung accumulation via intrapulmonary nebulization, active cellular targeting, and promoter-driven activation-to generate functionally optimized chimeric antigen receptor-expressing AMs (CAR-AMs). The CAR-AMs mediate synergistic antitumor efficacy through three integrated mechanisms: targeted phagocytosis of lung cancer cells, enhanced antigen presentation, and M1-like repolarization. Furthermore, CAR-AM-induced immune activation and memory potentiate the efficacy of immune checkpoint inhibitors and suppress metastatic progression in lung cancer models in female mice. This nanomedicine-based cell reprogramming strategy provides an approach to overcome immunosuppressive barriers in lung cancer immunotherapy and exemplifies the convergence of nanotechnology with immunology for enhanced therapeutic outcomes.

Trained immunity represents a paradigm shift in immunology, wherein innate immune cells acquire antigen-agnostic memory through epigenetic and metabolic reprogramming, enabling enhanced responses to secondary challenges. However, conventional trained immunity inducers have limitations including poor targeting, transient efficacy and systemic toxicity. Engineered nanoformulations including polymeric nanoparticles, inorganic carriers and nanovesicles can enhance inducer bioavailability, and prolong tissue retention. And it can achieve precise delivery to hematopoietic organs (bone marrow, spleen) or specific immune cells (macrophages, dendritic cells), amplifying trained immunity while mitigating off-target effects. Therapeutically, nano-optimized inducers demonstrate significant efficacy across pathologies including oncology, sepsis, autoimmune diseases and so on. In this article, we review the latest progress of nanomaterials-mediated trained immunity and its application in disease treatment. We focus on different nanomaterials used as specific training immune inducers. Subsequently, we describe the applications of nanomaterials-based trained immunity in different diseases. Finally, we look forward to the key challenges faced by nanomaterials-based training immunity and the directions for future development.

Antimicrobial-resistant (AMR) Gram-negative bacteria emerge due to the overuse of antibiotics. Moreover, current bactericidal drugs or materials inevitably associate with the immunologic risks from the lipopolysaccharide (LPS) released by dead bacteria, which initiates and exacerbates chronic tissue-destructive hyperinflammation, leading to treatment failure. In this study, we describe an orchestrated pH-sensitive cationic polymer nanoparticle encapsulated with rifampicin and toll-like receptor (TLR) siRNA (RNP/siRNA) that exhibits antibacterial and LPS-detoxifying characteristics for treating infected diseases. Under acidic conditions, RNP/siRNA nanoparticle releases rifampicin and cationic polymers displaying synergistically inhibitory activity against AMR bacteria by disrupting bacterial membranes, and facilitating the entry of antibiotics. Furthermore, RNP/siRNA nanoparticle exhibits high cellular uptake and TLR knockdown efficiency, thereby detoxifying the etiological LPS in M1-type macrophages polarization and reducing proinflammatory cytokines. In a mouse pneumonia model, RNP/siRNA nanoparticle treatment inhibits bacterial growth, suppresses inflammation and reduces leukocyte recruitment. In a rat periodontitis model, the administration of RNP/siRNA downregulates proinflammatory cytokines expression and inhibits bone resorption. This work highlights the elevated LPS release is an early trigger of hyperinflammation during the antibacterial process of currently established antimicrobials. The RNP/siRNA nanoparticle represents a promising strategy by integrating antibiosis and immunomodulation in a cascading manner for the treatment of bacterial infections.

Correction for 'A charge-adaptive nanosystem for prolonged and enhanced in vivo antibiotic delivery' by Liping Chu et al., Chem. Commun., 2016, 52, 6265-6268, https://doi.org/10.1039/c6cc01269h.

Adoptive cell transfer (ACT) therapy uses multifunctional immune cells to treat diseases such as autoimmune diseases and cancers. However, ACT still faces many problems in clinical application, such as high manufacturing costs and complexity, side effects such as cytokine release syndrome in cancer patients, neurotoxicity and off-target toxicity, and limited efficacy in solid tumors, which hinder its effective clinical transformation. Biomaterial technologies, some designed nanoparticles and hydrogels that can improve cell manufacturing, and the selected delivery of engineered immune cells in vivo have overcome some limitations of ACT. This chapter will mainly discuss the current research status of biomaterials-enhanced ACT for cancer treatment, and clarify the future improvement directions of biomaterials-enhanced ACT for cancer treatment.

Myocarditis is fundamentally characterized by the excessive infiltration of inflammatory cells (monocytes and macrophages) within the myocardium, posing a substantial risk of progressive cardiac dysfunction. Blocking the C-C motif chemokine receptor 2 (CCR2) pathway to curtail the infiltration of CCR2+ monocytes can suppress the immune response; nevertheless, these approaches may unwittingly impede the normal migration and activation of myeloid cells, potentially undermining the body's immune defenses. To address this backdrop, we designed itaconic acid liposomes (ITA-Lipo) to modulate the immune function of CCR2+ myeloid cells and thereby alleviate myocarditis. It was found that ITA-C4 Lipo could not only inhibit the differentiation of monocytes and macrophages into a pro-inflammatory phenotype but also significantly facilitate the hitchhiking migration toward the myocardium via enhancing the expression of CCR2. In the doxorubicin (DOX)-induced mice myocarditis model, ITA-C4 Lipo enhanced the homeostasis of myocardial cells and reduced relevant blood indicators. The cardiac function was recovered by improving left ventricular ejection fraction (LVEF) and ventricular fractional shortening (LVFS), resulting in the extension of overall mice survival. Anti-inflammatory pathway validation demonstrated that ITA-C4 Lipo can modulate the phenotype of macrophages and activate the KEAP1-Nrf2 pathway, reducing the expression of IL-1β. These findings underscore the significance of ITA liposomes in regulating the polarization of myeloid cells during their chemotaxis to the inflammatory focus, representing a promising therapeutic strategy for myocarditis.

Fractionated radiotherapy (FRT), typically delivering low-dose radiation of 2 Gy per fraction, has been used as the main clinical treatment regimen for various tumors. However, its therapeutic efficacy is severely hindered by inadequate pro-immunogenic effect and ionizing radiation-induced immunosuppression. Herein, a peptide nanoregulator (SPER-NO-Ind) is constructed from self-assembling peptides that can enrich nitric oxide (NO) at the endoplasmic reticulum (ER) and inhibit indoleamine 2,3-dioxygenase (IDO) to enhance FRT-mediated antitumor immunity and reinforce treatment outcomes. SPER-NO-Ind triggered S-nitrosylation of the ryanodine receptor by ER-specific enrichment of NO, triggering the release of Ca2+ within ER and induction of robust ER stress. The combination of 2 Gy gamma-radiation with SPER-NO-Ind induced intense immunogenic cell death (ICD) in ER-stressed 4T1 cells. Furthermore, this nanoregulator inhibited IDO and decreased kynurenine production, reversing FRT-induced immunosuppressive effects. The combined application of FRT and SPER-NO-Ind demonstrated superior efficacy in suppressing breast tumor growth, amplifying abscopal effects, and inhibiting metastasis in mice. The SPER-NO-Ind treatment achieved a 40% decrease in the total radiation dose while securing equivalent tumor suppression efficacy. Collectively, the work presents a facile approach to augment the efficacy of fractionated radiotherapy for tumors, opening up a new way to enhance the antitumor immune response of radiotherapy.

As a principal adjuvant therapy for glioblastoma (GBM), radiotherapy (RT) is instrumental in extending patient survival. Radiosensitizers could enhance the cytotoxic effects of radiation on tumor cells. However, their accumulation and penetration are significantly hindered by the blood-brain barrier (BBB) and weak convection and diffusion due to elevated interstitial pressure and the dense extracellular matrix within GBM, which reduces the effectiveness of RT. To maximize the radiosensitizing efficiency, it is imperative to develop a delivery system capable of crossing the BBB, specifically targeting GBM, and penetrating the center of the GBM. We propose utilizing cell membrane camouflage to achieve BBB crossing and tumor targeting and the self-propulsion ability of nanomotors to promote diffusion and overcome convection within GBM, thereby facilitating deep tumor penetration. We first clarify that the hollow structure with an opening exhibits a stronger propulsive force than the Janus structure under identical conditions. Subsequently, we developed a facile method to prepare nanomotors featuring a hollow structure with an opening. By camouflaging the nanomotors with hybrid cell membranes with BBB-crossing and tumor-targeting capabilities, we create biomimetic nanomotors (Bio-motors). Results show our Bio-motors possess enhanced diffusion capacity and achieve deep penetration under reverse pressure gradients, which also effectively traverse the BBB, target GBM, and penetrate deeply within the tumor. Notably, the Bio-motors enhance radiosensitivity and inhibit GBM growth, thereby prolonging the median survival of GBM-bearing mice. Our Bio-motors will significantly boost RT efficacy for GBM patients and could be readily adapted into versatile carriers for tumor therapy due to the modular design.

Supramolecular hydrogels of self-assembling peptide-drug conjugates have been considered as effective self-delivery drug systems for cancer therapy in recent years. Here, a novel self-assembling peptide-based supramolecular hydrogel was developed by simultaneously conjugating small-molecule drug chlorambucil (CRB) and peptide drug tyroservatide (YSV) to the self-assembling peptide. The resulting hydrogel with a nanofiber structure showed enhanced stability against proteinase K degradation and an improved cellular uptake performance in comparison with the free molecules. As a consequence, it exhibited enhanced antitumor efficiency both in vitro and in vivo with favorable biocompatibility. This biocompatible self-delivery drug system could not only significantly improve the delivery efficiency of the small-molecule drugs but also adequately synergize the antitumor effect of CRB and YSV, inspiring the design of new strategies of cancer combination therapy.

Purpose/Objective(s) The prognosis of nasopharyngeal carcinoma with T4 or N3 remains unsatisfactory. The aim of this study was to assess the efficacy and safety of neoadjuvant with GP plus tislelizumab followed by concurrent chemoradiotherapy, and adjuvant treatment with tislelizumab, an anti-PD-1 monoclonal antibody, in previously untreated stage IVA (T4 or N3) nasopharyngeal carcinoma. Materials/Methods In this phase II, single-arm study, eligible patients aged 18-70 years who were diagnosed with stage IVA (AJCC 8th) non-keratinizing nasopharyngeal carcinoma received neoadjuvant therapy with gemcitabine (1000mg/m2 on day 1,8), cisplatin (25 mg/m2 on day 1-3) and tislelizumab (200mg) Q3W for 2 cycles followed by concurrent IMRT and cisplatin (100 mg/m2) Q3W during radiotherapy, then followed by adjuvant therapy with tislelizumab (200 mg) Q3W for 13 cycles. The primary endpoint was 2-year progression-free survival (PFS). The secondary endpoint included objective response rate (ORR), overall survival (OS) and safety. Results A total of 55 patients were enrolled from Sep. 2021 to Jun. 2023 with a median age of 43 (22-66) yrs and 76.4% (n = 42) of male. T4 account for 43.6% and N3 account for 67.3%. After a median follow-up of 16 months, 7 patients experienced disease progression with one patient in local relapse, three patients in regional relapse and three patients in distant metastasis. One-year PFS rate was 89.7%, and 1-year OS rate was 100%. According to RECIST1.1, 48 (87.3%) patients had objective response to neoadjuvant treatment, including 9 (16.4%) patient with CR, 39 (70.9%) patients with PR. The other 7 (12.7%) patients had SDa with a definition of tumor shrinkage occurred and below a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Throughout the neoadjuvant phase, 23 (41.8%) patients experienced grade 3-4 treatment-related adverse events (TRAE), with the most common being nausea (9[16.4%]) and leukopenia (8[14.5%]). Grade 3-4 TRAE appeared in 15 (27.3%) patients during concurrent chemoradiotherapy, with the most common being leukopenia (7[12.7%]) and mucositis (5[9.1%]). Conclusion For stage IVA nasopharyngeal carcinoma patients, neoadjuvant with tislelizumab plus GP and adjuvant tislelizumab treatment is safe and promising. Further follow-up is needed to confirm the long-term efficacy.

The radiation-induced skin injury (RISI) remains a great challenge for clinical wound management and care after radiotherapy, as patients will suffer from the acute radiation injury and long-term chronic inflammatory damage during the treatment. The excessive ROS in the early acute stage and prolonged inflammatory response in the late healing process always hinder therapeutic efficiency. Herein, we developed an extracellular matrix (ECM)-mimetic multifunctional glycopeptide hydrogel (oCP@As) to promote and accelerate RISI repair via a dual-modulation strategy in different healing stages. The oCP@As hydrogel not only can form an ECM-like nanofiber structure through the Schiff base reaction but also exhibits ROS scavenging and DNA double-strand break repair abilities, which can effectively reduce the acute radiation damage. Meanwhile, the introduction of oxidized chondroitin sulfate, which is the ECM polysaccharide-like component, enables regulation of the inflammatory response by adsorption of inflammatory factors, accelerating the repair of chronic inflammatory injury. The animal experiments demonstrated that oCP@As can significantly weaken RISI symptoms, promote epidermal tissue regeneration and angiogenesis, and reduce pro-inflammatory cytokine expression. Therefore, this multifunctional glycopeptide hydrogel dressing can effectively attenuate RISI symptoms and promote RISI healing, showing great potential for clinical applications in radiotherapy protection and repair.

Radiosensitizers hold great promise for enhanced cancer radiotherapeutics. However, apoptosis evasion of cancerous cells usually limits the efficiency of radiosensitive strategies. Herein, an in situ self-assembled supramolecular antagonist is developed to reinforce the treatment outcome of radiotherapy by inhibiting tumor apoptosis evasion. The supramolecular antagonist is composed of self-assembled peptide functionalized with apoptosis-inducing peptide SmacN7 and alkaline phosphatase (ALP)-responsive group. Upon reaching the tumor site, the supramolecular antagonist can in situ form membrane-localized nanofibers triggered by ALP overexpressing in tumor cells, leading to enhanced cellular internalization. As a result, the cell-permeable supramolecular antagonist effectively binds to the inhibitor of apoptosis proteins (IAPs) and eliminates their inhibitory effect on caspase activity, thereby remarkably blocking the apoptosis evasion of tumor cells and boosting the therapeutic efficacy of radiotherapy. Furthermore, in vivo studies confirm that treatment with in situ self-assembled supramolecular antagonists can enhance radiation-induced tumor destruction without perceptible systemic toxicity. This study offers a novel strategy of tumor apoptosis evasion inhibition to potentiate radiotherapy, which may be instructive to the development of advanced cancer therapies.

Tumor cells elicit metabolic reprogramming to establish an immunosuppressive tumor microenvironment (TME) for escaping from immunosurveillance. Therefore, interrupting the metabolic adaptation of tumor cells may be a promising strategy for TME immunomodulation, favoring immunotherapy. In this work, a tumor-specific peroxynitrite nanogenerator APAP-P-NO is constructed that can selectively disrupt metabolic homeostasis in melanoma cells. Stimulated by melanoma-characteristic acid, glutathione, and tyrosinase, APAP-P-NO can efficiently generate peroxynitrite through the in situ coupling of the produced superoxide anion and released nitric oxide. Metabolomics profiling reveals that the accumulated peroxynitrite induces a great decrease in metabolites in the tricarboxylic acid cycle. Meanwhile, the glycolysis-produced lactate drops sharply both intracellularly and extracellularly under peroxynitrite stress. Mechanistically, peroxynitrite impairs the activity of glyceraldehyde-3-phosphate dehydrogenase in glucose metabolism through S-nitrosylation. The metabolic alterations effectively reverse the immunosuppressive TME to evoke potent antitumor immune responses, including polarization of M2-like macrophages to M1phenotype, reduction of myeloid-derived suppressor cells and regulatory T cells, and restoration of CD8+ T cell infiltration. Combining APAP-P-NO with anti-PD-L1 achieves a significant inhibition against both primary and metastatic melanomas without systemic toxicities. Collectively, a tumor-specific peroxynitrite overproduction approach is developed and the possible mechanism of peroxynitrite-mediated TME immunomodulation is explored, providing a new strategy for facilitating immunotherapy sensitivity.

Natural resistance and biofilm formation make Pseudomonas aeruginosa (P. aeruginosa) highly infectious worldwide. Fighting against P. aeruginosa in biofilms has been a long challenge. Herein, P. aeruginosa-targeting nanoassemblies (PGPF@ICG) are designed by encapsulating indocyanine green (ICG) into farnesol-decorated poly(D-glucose)-block-poly(hydroxyethyl methylacrylate) (denoted PGPF). First, PGPF@ICG can effectively permeate into the biofilm of P. aeruginosa and subsequently target LecA. Under 808 nm laser irradiation, PGPF@ICG can change membrane potentials and improve the ROS level of internal bacteria and biofilms to effectively kill P. aeruginosa and eliminate biofilms. Meanwhile, farnesol released from PGPF by the cleavage of the oxalic bond in the inflammatory environment further reinforced antibacterial efficacy and remodelled the inflammatory environment by downregulating M1 macrophages and their related inflammatory factors. Through infected site delivery, PGPF@ICG+NIR showed antibacterial and anti-inflammatory effects superior to those of the other groups in P. aeruginosa-infected wound and subcutaneous cyst models. Furthermore, the innate immune response of the infected site is remodelled by PGPF@ICG+NIR, as evidenced by accelerating the healing of the infected site and new angiogenesis, as well as reducing inflammation. Therefore, the biocompatible PGPF@ICG targets biofilms and bacteria, as well as remodels innate immunity in a cascade manner, providing a new strategy for the treatment of P. aeruginosa-infected diseases.& COPY; 2023 Elsevier Ltd. All rights reserved.

Radiotherapy is one of the most important means of cancer treatment, however, radiation can also cause adverse reactions and even serious injuries to the skin. Radiation-induced excess reactive oxygen species (ROS) production and inflammatory infiltration make skin wounds difficult to heal compared to normal skin injuries. Herein, an antioxidant heparin-mimetic peptide hydrogel (K16, KYKYEYEYAGEGDSS-4Sa) is designed for radiation-induced skin injury (RISI) repair. First, the K16 peptide can self-assemble into a hydrogel with a 3D mesh-like porous nanofiber structure, which can provide certain physical support for skin repair like extracellular matrix (ECM). Then, K16 hydrogel not only scavenges ROS and prevents radiation damage to cellular DNA, but also promotes cell proliferation, migration, and angiogenesis. Meanwhile, 4-sulfobenzoic acid (4Sa) modified at the N-terminal end of the K16 peptide can adsorb inflammatory cytokines, thus acting to eliminate inflammation at the wound site. In vivo experiments showed that K16 hydrogel can inhibit early wound degradation, reduce inflammatory infiltration, and promote angiogenesis and collagen deposition, thus promoting wound healing. Therefore, the K16 hydrogel designed in this study has good potential for application in the field of radiation-induced skin injury repair.