Immunosuppressive tumor microenvironment remains a major obstacle to effective cancer immunotherapy, largely due to insufficient initiation and amplification of antitumor immune responses. Herein, we report a mechanism-driven nanotherapeutic strategy that establishes a self-amplifying cuproptosis–STING cascade to overcome tumor immune resistance. The multifunctional copper/manganese-phenolic nanocapsules (HLCM@Cap) undergo pH-responsive release in the acidic tumor microenvironment, enabling efficient intratumoral copper accumulation and triggering cuproptosis characterized by mitochondrial dysfunction and proteotoxic stress. The resulting release of mitochondrial DNA activates the cGAS-STING pathway, while concurrently released Mn2+ further amplifies STING signaling. Meanwhile, Mn2+ also enables T1-weighted magnetic resonance imaging for real-time monitoring of intratumoral nanocapsule accumulation and release, allowing optimization of the administration window. To counteract tumor adaptive resistance, a Wnt/β-catenin inhibitor is incorporated to suppress glycolytic reprogramming and copper efflux, thereby enhancing intracellular copper toxicity and metabolic stress. This coordinated regulation forms a positive feedback loop that reinforces STING activation through persistent damage-associated signaling. Consequently, the cascade promotes dendritic cell maturation, enhances CD8+ T cell infiltration, remodels the immunosuppressive tumor microenvironment, and induces durable immune memory. In a 4T1 tumor model, HLCM@Cap achieves significant antitumor and antimetastatic effects, which are further enhanced in combination with αPD-L1 therapy. Overall, this work presents a self-amplifying cuproptosis–STING cascade to convert immunologically “cold” tumors into “hot” tumors, offering a promising and translatable strategy for synergistic cancer immunotherapy.

Circulating tumor cells (CTCs) hold great promise as biomarkers for cancer diagnosis, metastasis assessment, and therapeutic monitoring. However, their extremely low abundance and interference from complex blood components make their efficient and specific isolation highly challenging. Herein, we developed a reduction-responsive, antifouling, and cell-mimicking silica-patterned platform functionalized with bispecific antibodies (BsAbs, anti-PEG scFv, and anti-HER2 scFv) for selective CTC capture. The PEG-modified surface effectively suppressed nonspecific adhesion of immune cells, while the BsAbs and rough substrate topology synergistically enhanced the capture efficiency and specificity toward HER2-overexpressing tumor cells (SKBR3). Notably, the captured cells could be gently released upon treatment with glutathione, preserving their viability for subsequent culture and analysis. This study provides a robust and controllable strategy for highly-specificity CTC isolation, offering a promising tool for liquid biopsy-based cancer diagnostics.

Cancer vaccines have proven to be a powerful tool in anti-tumor immunotherapy, leveraging antigen-specific T-cell responses. The effective activation of the stimulator of the interferon gene (STING) protein signal pathway by natural or synthetic agonists leads to the creation of a pro-immune tumor microenvironment. Here, we report the preparation of ovalbumin (OVA) loaded cancer vaccines based on nanoemulsions, denoted as DMMF59-OVA, for the co-delivery of antigens and a STING agonist (MSA-2). The nanovaccines were obtained via encapsulation of MSA-2 into squalene phase, which was stabilized by surfactants and coated with OVA. Upon intramuscular administration, the engineered nanovaccine facilitates antigen internalization, maturation of antigen-presenting cells (APCs), and efficient activation of the STING pathway. These results in enhanced antigen-specific humoral and cellular immune responses that significantly inhibit tumor growth in an E.G7-OVA mouse model. The studies provide an avenue for the application of nanovaccine in tumor immunotherapy. Given the ease of preparation and tunable physicochemical properties, DMMF59-OVA represents a promising therapeutic nanovaccine for biomedical applications

PEGylated liposomes are widely used as drug delivery carriers due to their prolonged circulation and enhanced accumulation at pathological sites. However, repeated administration can trigger the accelerated blood clearance (ABC) phenomenon, reducing delivery efficacy. Herein, we report a zwitterionic PEGylation strategy by grafting glutamic acid-lysine (EK) peptides onto PEGylated phospholipid derivatives to assemble liposome (Lip)-based drug delivery systems. Small-angle neutron scattering analysis confirmed that EK modification significantly enhanced Lip hydration, leading to a 40-fold reduction in protein adsorption compared to conventional PEGylation, which therefore reduced immune cell uptake, anti-PEG antibody production, and nonspecific hepatic accumulation of EK-Lip. Furthermore, even in the presence of preexisting APAs, EK-Lip could mitigate the ABC effect and exhibit a twofold increase in the area under the curve of the pharmacokinetic profile after multiple injections compared to Lip. When loaded with doxorubicin, the zwitterionic EK-Lip demonstrated lower immunogenicity and superior antitumor efficacy compared to conventional formulations. This work provides a facile strategy to assemble zwitterionic liposomes with modified surface chemistry, offering a promising solution to the ABC effect in PEGylated liposomes.

Glioblastoma multiforme (GBM) as the most prevalent primary malignant brain tumor shows nearly universal recurrence following surgical resection. Tumor-treating fields (TTF), a promising and clinical therapy for GBM, may trigger antitumor immunity, as suggested by growing evidence. Herein, we uncover the TTF-triggered immunogenic cell death (ICD) at single-cell RNA sequencing resolution in GBM through sphingolipid-metabolism-associated pathway-mediated endoplasmic reticulum stress. Further, an ATP-responsive hydrogel adjuvant (Ha) was designed to synergize with TTF for spatiotemporally controlled release of antigens and CpG, reactivating myeloid cell interaction networks and augmenting sustained antitumor responses. The Ha-complemented TTF therapy (HaTTF) could effectively suppress tumor growth in GBM-bearing rats, outperforming TTF therapy, which merely delayed progression. This study establishes an adjuvant-enhanced tumoricidal immunity platform integrating TTF, with potential applications across various malignant solid tumors.

Lightweight porous materials hold immense potential across industrial and biomedical applications, while conventional fabrication methods face challenges including energy-intensive drying processes, structural collapse, and limited mechanical strength. Herein, we report a universal strategy to engineer robust dry foams stabilized by metal-phenolic networks (MPNs) through a synergistic combination of high-speed mechanical foaming and freeze-thaw drying process. By introducing carboxymethyl chitosan (CMCS) and metal ions for rapid cross-linking, the foam templates can be stabilized to overcome the instability of conventional foams, enhancing solvent exchange efficiency and achieving hierarchical porosity. The integration of metal-phenolic coordination during the freeze-thaw process further reinforces the CMCS skeletal framework, yielding materials with exceptional mechanical integrity (<16% shrinkage and >80 kPa Young's modulus) and ambient-drying compatibility. The resultant MPN-stabilized dry foams (MPN foams) exhibit excellent antibacterial activity and angiogenesis promotion for wound healing applications.

Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy has been widely used for non-muscle-invasive bladder cancer treatment. However, it remains challenging due to the high recurrence rate and inadequate response in a substantial proportion of patients. Herein, we report a facile approach to engineer BCG with metalphenolic networks (MPNs), denoted as BCG@MT-A, which can co-deliver a STING agonist (i.e., Mn2+) and a CXCR4 antagonist (i.e., AMD3100) for bladder cancer therapy. The MPN coating significantly improved mucoadhesion and prolonged bladder retention, while the acidic tumor microenvironment triggered the release of Mn2+ and AMD3100. Released Mn2+ potently activated dendritic cells via the STING pathway, and AMD3100 inhibited tumor proliferation and induced immunogenic cell death by blocking the CXCL12/CXCR4 axis. Intravesical instillation of BCG@MT-A significantly suppressed tumor growth, promoted infiltration of CD8+ T cells and mature dendritic cells, reduced immunosuppressive cells, and enhanced antitumor cytokine secretion. The reported surface engineering strategy synergistically enhances BCG immunotherapy and represents a promising translational approach for improving clinical outcomes in bladder cancer therapy.

One of the major challenges in the development of active targeting nanomedicines is the plasma protein corona (PC), which might interfere with or diminish the targeting function. A novel strategy has emerged by precisely regulating the PC through the utilization of endogenous proteins, which is possible to transform the PC into an integral component that enhances targeting ability. However, the individual variability and fluctuating concentrations of endogenous proteins in plasma limit its practical application. In this study, we employed a bispecific antibody (BsAb) integrating mPEG-scFv (a single chain variable fragment to methoxy polyethylene glycol) and HER2-scFv (human epidermal growth factor receptor 2 scFv) to assembly with liposome. By pre-engineering the PC of liposomes, the targeting function to HER2+ cells could be preserved during circulation. Notably, the PC formed by BsAb competitively inhibited the binding of endogenous anti-PEG antibodies, thereby reducing subsequent complement activation and alleviating the accelerated blood clearance (ABC) effect. In tumor-bearing mice, BsAb-sLip demonstrated significant accumulation in HER2+ human ovarian cancer cells (SKOV3). In the presence of anti-PEG antibodies after liposome stimulation in mice, BsAb significantly mitigated the ABC effect with prolonged liposome circulation. Consistently, in human serum containing pre-existing anti-PEG antibodies, BsAb suppressed liposome-induced complement activation, inhibited macrophage phagocytosis, and maintained the targeting ability toward HER2+ tumor cells. These findings indicated that the engineered PC strategy via BsAb represented an effective targeting approach improving the overall in vivo performance of nanomedicines.

Diabetic bone defects are not merely a consequence of impaired bone formation, but a complex syndrome driven by chronic hyperglycemia, characterized by dysregulated bone metabolism, vascular impairment, immune imbalance, and notably, aberrant activation of ferroptosis in osteoblasts. These multifaceted pathologies pose a major challenge in orthopedic treatment. In this study, we report the development of a metal-polyphenol synergistic hydrogel platform (HES) designed to address the unique demands of diabetic bone regeneration. Epigallocatechin gallate (EGCG) and strontium ions (Sr2+) are self-assembled into bioactive metal-phenolic network (MPN) nanoparticles (EGCG-Sr2+ NPs), which are uniformly integrated into a three-dimensional hyaluronic acid (HA) hydrogel matrix. This platform achieves spatiotemporal coordination of EGCG-mediated antioxidation and Sr2+-driven angiogenesis, while EGCG chelates metal ions to inhibit ferroptosis by scavenging ROS, sequestering Fe3+, protecting GPX4, upregulating HO-1, and suppressing lipid peroxidation. Additionally, EGCG exerts anti-inflammatory effects, and Sr2+ promotes angiogenesis, collectively enhancing osteogenic differentiation and tissue repair. Overall, this multifunctional hydrogel integrates ferroptosis inhibition, antioxidation, immunomodulation, and osteoinduction, offering a promising therapeutic strategy for effective repair of diabetic bone defects.

Near-infrared II (NIR-II) imaging-guided photothermal therapy (PTT) represents a promising noninvasive strategy for treating bacterial infections. However, its efficacy is often limited by poor agent accumulation at infection sites and insufficient penetration into biofilms. Herein, we developed stiffness-tunable phenolic nanocapsules (NCs) loaded with NIR-II J-aggregates for enhanced biofilm phototherapy. Specifically, the NIR-II photothermal molecule of BTPTIC was synthesized and assembled with 8-arm-PEG-OH to form J-aggregates (BTPTIC@PEG J-aggregates). The BTPTIC@PEG J-aggregates were used as mineralizers to synthesize zeolitic imidazolate framework-8 (ZIF-8), followed by template etching with tannic acid (TA) to obtain J-aggregate-loaded phenolic NCs (BTPTIC@PEG-TA NCs). The resulting NCs not only display strong NIR-II fluorescence and a high photothermal conversion efficiency up to 82.1% but also exhibit tunable stiffness by varying TA concentration. Notably, we demonstrate that softer NCs achieve superior accumulation in infected tissues and deeper penetration into bacterial biofilms, leading to a significantly enhanced antibacterial performance. Furthermore, the NCs exhibit pH-responsive degradation within acidic infection microenvironments, releasing TA with potent anti-inflammatory activity. This synergistic integration of NIR-II imaging-guided high-efficiency PTT and inflammation modulation enables the effective treatment of both superficial (e.g., wounds) and deep-tissue (e.g., pneumonia) bacterial infections. This work highlights carrier stiffness as a crucial design parameter for developing advanced antimicrobial nanotherapeutics.

Multiple emulsions enable the advanced encapsulation of active ingredients, making them favorable in cosmetic formulations. In this study, natural protein casein is employed to facilitate the ultrasound-assisted encapsulation of emollient-free, full-active sunscreen ingredients (FASI) comprising only three organic UV filters within an O/W emulsion. This O/W emulsion is further structured into a highly stable O/W/O emulsion gel. Rheological analysis confirms that the O/W/O emulsion exhibits gel-like behavior and shear-thinning properties, contributing to improved spreadability and skin feel. The encapsulation of sunscreen ingredients within the gel significantly enhances water resistance (>99%), UV protection efficacy, and overall safety. UV protection assays demonstrate the effective shielding of the O/W/O sunscreen against UV-induced damage to cells. This work presents a promising strategy for developing O/W/O sunscreens that minimize the use of organic UV filters, eliminate emollients, reduce water leakage, and limit bioaccumulation of active ingredients.

Polyphenols are natural compounds with diverse biological activities; however, their practical applications are often limited by poor solubility and chemical instability. In this study, a high-frequency ultrasound-assisted approach is developed for the preparation of polyphenol nanoparticles (NPs), producing well-dispersed and uniformly sized particles. The method exhibits excellent versatility and can be applied to a wide range of polyphenol precursors, including 1,8-dihydroxynaphthalene (1,8-DHN). Additionally, the integration of an ultrasound-assisted Fenton reaction markedly accelerates polyphenol polymerization and NP nucleation. The resulting NPs demonstrate outstanding antioxidant capacity, effectively scavenging intracellular reactive oxygen species (ROS). Notably, DHN-derived NPs show strong antibacterial activity, efficiently eliminating both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria at relatively low concentrations. Overall, this study presents a green, simple, and scalable strategy for fabricating multifunctional polyphenol NPs. The synergistic antioxidant and antibacterial properties of these NPs highlight their broad potential in biomedical engineering, providing a valuable platform for the design of next-generation bioactive nanomaterials.

Photodynamic therapy (PDT) offers the distinctive advantage of repeatable treatment without cumulative systemic toxicity. However, clinical translation is hindered by oxygen dependency, photothermal leakage, and immune clearance during multiple administrations. Here we report a next-generation photodynamic nanoplatform (KD1-loaded hyaluronic acid-poly(ethylene glycol) nanoparticles, KD1@HPEG NPs), an immune-evasive near-infrared II (NIR-II) photodynamic nanoplatform that integrates Type I photochemistry, deep-tissue fluorescence imaging, and stealth surface engineering to sustainable and precise PDT. The thiopyrylium photosensitizer KD1 incorporates a rigid electron-donating substituent that induces pronounced orbital reconfiguration, thereby enhancing intersystem crossing while suppressing nonradiative decay. This design enables efficient type I reactive oxygen species generation with negligible heat release. KD1@HPEG NPs further improve the stability of KD1, prevent anti-PEG antibody formation to circumvent the accelerated blood clearance effect, and impart intrinsic tumor affinity. These molecular and immunological optimizations support oxygen-independent ROS generation, sustained NIR-II imaging, and preserved therapeutic efficacy under repeated dosing. KD1@HPEG NPs establish a generalizable strategy for long-term, immune-tolerant PDT and offers a clinically viable platform for durable, precision phototheranostics.

Atherosclerosis (AS), the leading cause of cardiovascular diseases (CVDs), is characterized by endothelial injury, lipid accumulation, cell apoptosis and excessive production of intravascular reactive oxygen species (ROS). Conventional AS therapies often require high doses, show only moderate efficacy, and are associated with side effects, highlighting the need for targeted drug delivery strategies. Previous studies have demonstrated that Dickkopf-1 (DKK1) is highly expressed in AS lesions and plays a critical role in regulating endothelial function, lipid metabolism, and angiogenesis in AS. Herein, L-Arginine (L-Arg) was, for the first time, used to assist the assembly of Epigallocatechin gallate (EGCG) via a Mannich condensation reaction, generating functionalized EGCG-Arg nanodrugs (E/A NDs). E/A NDs were subsequently loaded with Mn2+ and coated with DKK1 antibody to synthesize targeted diagnostic and therapeutic nanodrugs (E/A-Mn2+@D NDs). In vitro studies showed that E/A-Mn2+@D NDs efficiently inhibited ROS production, cell apoptosis, inflammatory macrophages polarization and foam cell formation. In an apolipoprotein E-deficient (ApoE−/−) mouse model of AS, treatment with E/A-Mn2+@D NDs significantly inhibited the progression of atherosclerotic lesions and improved plaque stability, as evidenced by reduced lipid deposition, decreased macrophage infiltration and matrix metalloproteinase-9 (MMP-9) expression, and increased collagen content. Moreover, both in vivo and ex vivo experiments demonstrated excellent atherosclerotic plaque imaging capability and low toxicity of E/A-Mn2+@D NDs. Together, our study presents a novel assembly E/A-Mn2+@D NDs for integrated AS diagnosis and therapy, which may also be applicable to other DKK1-overexpressing diseases.

Osteoporotic fracture healing is trapped in a vicious cycle where multiple pathological factors, including persistent oxidative stress, inadequate vascular supply, and an imbalance bone remodeling process that favors resorption, combine to form a hostile niche for regeneration. The intricate interaction of these pathologies highlights the need to transform titanium implants from inert devices into active platforms for bone regeneration. In this study, a multifunctional coating where titanium dioxide nanotubes (TNT) are decorated with metal-organic networks (TNT@EZCA) is developed for coordinated regulation of pathological processes. The metal-organic network, composed of EGCG, Zn2 +, Ca2 +, and ALN, is engineered to orchestrate a pro-regenerative microenvironment that concurrently targets oxidative stress, angiogenesis, and bone homeostasis. In vitro studies confirm that the coating effectively scavenges reactive oxygen species, promotes endothelial cell functions, and re-establishes the balance between osteoblast and osteoclast. In an osteoporotic fracture model, TNT@EZCA significantly accelerates bone regeneration, improves bone microstructure and callus vascularization, and exerts a systemic osteoprotective effect. This study demonstrates that a multifunctional and integrated regulatory strategy effectively drives a systemic osteoprotective effect involving vascular network reconstruction and bone homeostasis restoration, offering a potential therapeutic strategy for improving the healing of osteoporotic fractures.

Monoterpene phenols have antibacterial, antioxidant, anticancer, antihypertensive, and antidiabetic properties, but their natural volatility and hydrophobicity limit their biomedical applications. In this work, we developed an oil-in-water nanoemulsion (NE) stabilized by proteins (i.e., sodium caseinate, NaCas) and polyphenols (i.e., tannic acid, TA) using phacoemulsification, where thymol (TH) was dissolved in carvacrol (CA) and the mixture was used as the dispersed phase. The NE avoids the use of traditional surfactants as the stabilizer. Amphiphilic NaCas could stabilize the NE, followed by further cross-linking of NaCas using TA. These antimicrobial agents of monoterpene phenols were efficiently encapsulated in NE to enhance their colloidal stability in aqueous solution. The resulting NE showed strong antibacterial activity, reduced inflammation ability, and improved healing of bacteria-infected wounds. TA acted as both an NE stabilizer and a synergistic agent to boost antibacterial effects and accelerate wound repair. This work demonstrates a promising strategy for delivering natural antimicrobial agents of monoterpene phenols to treat infected wounds.

Osteoporosis fractures are typically difficult to heal due to excessive and persistent inflammatory activation, hyperactivated osteoclast activity, compromised osteogenic differentiation capacity, and diminished angiogenic potential. Local delivery of therapeutics to promote immunomodulation with enhanced osteogenic differentiation and inhibition of osteoclasts is promising for the repair of osteoporotic fractures. Herein, we report the preparation of poly(ethylene glycol) (PEG)‐alendronate‐magnesium (PAMg) hydrogels by mixing alendronate (ALN)‐conjugated 8‐arm‐PEG‐NHS with magnesium ions (Mg 2+ ) and 8‐arm‐PEG‐NH 2 based on amide formation and metal coordination. The reversible cross‐linking strategy is not only beneficial for the hydrogel formation but also for the release of ALN and Mg 2+ during the hydrogel degradation, which effectively combines the functions of ALN and Mg 2+ . Consequently, the hydrogel can balance osteogenesis and osteoclastogenesis by modulating the immune microenvironment for bone regeneration. Specifically, it effectively promotes the repair of osteoporotic bone defects by inhibiting osteoclast differentiation while simultaneously enhancing osteogenesis and angiogenesis. This study highlights the potential of PAMg hydrogels for treating osteoporosis‐related bone defects, offering new prospects in bone tissue engineering for biomedical applications.

Stiffness, as a crucial physicochemical property of nanoparticles (NPs), has demonstrated a significant impact on bio-nano interactions, including blood circulation, biodistribution, tumor accumulation, and cellular uptake. However, the potential role of NP stiffness in modulating bio-nano interactions to potentiate drug delivery efficacy remains largely unexplored. In this study, poly(ethylene glycol) (PEG) NPs are engineered by the sophisticated layer-by-layer (LbL) assembly approach, and the Young's moduli of NPs in the range of 2-31 kPa are tuned by control over the bilayer numbers. Notably, softer PEG NPs resulted in less adsorption of the protein corona and cell association. The half-life of blood circulation time of PEG NPs decreases along with the increase in stiffness/bilayer number of NPs, while the accumulation of PEG NPs in the liver is contrary to the case. In addition, stiffness influences the targeted drug delivery efficacy, where softer PEG NPs modified with hyaluronic acid exhibited higher cell targeting and tumor accumulation as well as better inhibition of tumor growth. This work highlights the bilayer number-mediated stiffness of NPs and the vital role of stiffness in bio-nano interactions, which provides a promising approach to design nanocarriers for improved drug delivery efficacy.