Bozhao Li

Uncontrolled hemorrhage in trauma, surgical, organ-related, and endoscopic settings, particularly in patients receiving antiplatelet therapy, remains difficult to manage clinically. Here, we introduce a high phosphatidylserine (PS)–exposed procoagulant platelet (hPPL) derivative reprogrammed from isolated platelets via calcium ionophore A23187–induced apoptosis, enriched in surface PS and capable of driving rapid hemostasis. Retaining a protein profile akin to resting platelets, hPPLs robustly promoted platelet activation and aggregation in human- and rat-derived plasma and whole blood in vitro and demonstrated superior hemostatic efficacy compared with clinical thrombin and commercial hemostatic materials [microporous polysaccharide hemispheres (MPH) and FIBRILLAR] in murine liver injury and porcine gastric ulcer bleeding models, even under antiplatelet treatment. Mechanistically, hPPLs up-regulated prostaglandin E synthase (PTGES), thereby increasing prostaglandin E2 (PGE ₂ ) production and its receptor 3 (EP3)–mediated platelet activation, which reinforced PS-mediated clot formation. Our findings identified an apoptosis-driven PTGES-PGE ₂ -EP3 signaling axis that augmented PS-mediated coagulation in murine and porcine hemorrhage models and established the hPPL derivative as a topical hemostatic agent with translational potential for organ-related bleeding and distinct advantages in managing complex endoscopic hemorrhages under both physiological and coagulopathic conditions.

Natural biological systems achieve precise cellular control through multidimensional signaling architectures that integrate sequence specificity, structural dynamics, and conformational switching. While synthetic DNA networks have been engineered primarily using sequence programmability, exclusive reliance on this dimension constrains signaling range and integrated regulation. Here, we report an allosteric DNA computing framework enabling the simultaneous integration of sequence programmability with conformational dynamics for integrated multilevel signal processing. By encoding conformational signals within polythymidine loops (0 to 40 nucleotides), this system executes loop-dependent logic operations with expanded signaling ranges. Moreover, catalytic allosteric hairpin assemblies achieve ~30-fold signal amplification with enhanced signal-to-noise ratios. Concurrently, allosteric DNA neural networks discriminate conformational signals based on loop lengths (7 to 15 nucleotides) at two-nucleotide resolution. Crucially, microRNA-responsive versions of this framework regulate gene expression, thereby bridging conformational signaling with genetic control regulations in vivo. Collectively, this work establishes a conformational signal-processing paradigm for adaptive DNA computing, paving the way for advanced synthetic biology and precision therapeutics.

Supporting information for manuscript

Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)–positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.Significance:A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.

Supporting information for manuscript

Nanoparticles (NPs) spanning diverse materials and properties have the potential to encapsulate and protect a wide range of therapeutic cargos to increase bioavailability, prevent undesired degradation, and mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader (SERD), is commonly used for treating estrogen receptor (ER)-positive breast cancer patients, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. Additionally, the NP was co-loaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.

Supporting information for manuscript

Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)–positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.Significance:A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.

Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)–positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer. Significance: A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.