The persistent opening of the mitochondrial permeability transition pore (mPTP) plays a critical role in bronchial asthma pathogenesis. The ATP synthase c subunit (c subunit) constitutes a core component of mPTP. A novel c subunit inhibitor, 1,3,8-triazaspiro [4.5] decane derivatives (PP10), effectively suppresses pathological mPTP opening without impairing ATP synthesis. Although intraperitoneal PP10 administration mitigates airway inflammation in asthmatic mice, its hydrophobicity hinders inhaled delivery to airway epithelial mitochondria, requiring penetration of the mucus layer, cell membrane, and mitochondrial outer membrane. To overcome this, we developed inhalable human serum albumin-triphenylphosphine-polyethylene glycol-PP10 nanoparticles (HSA-TPP-PEG-PP10 NPs). These NPs demonstrated efficient mucus penetration, high drug loading, mitochondria-targeting capability, and biosafety. They suppressed house dust mite/lipopolysaccharide (HDM/LPS)-induced mPTP opening, inhibited the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, reduced inflammation in human bronchial epithelial (HBE) cells, and alleviated airway inflammation in asthmatic mice upon inhalation.

This study investigated (pre)clinically the biodistribution of the tri-specific Humabody® CB307, composed of three heavy variable domains (VHs) targeting prostate-specific membrane antigen (PSMA), CD137, and human serum albumin (HSA). CB307 internalization was assessed in PSMA- and CD137-positive tumor and T-cells. In xenograft mouse models bearing PSMA-positive and PSMA-negative tumors biodistribution of 99mTc-PSMA-targeting VHs bound/unbound to mouse serum albumin (MSA) and full-length 99mTc-PSMA monoclonal antibody J591 was assessed by SPECT. Five patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) underwent baseline 18F-PSMA-PET scans to define PSMA-positive lesions, followed by 89Zr-CB307 (37 MBq/5 mg) administration and escalating doses of unlabeled CB307, up to 100 mg. PET was performed at multiple time points. Spherical VOIs were manually drawn around tumors and organs to calculate standardized uptake values (SUVs). Additionally, tumor biopsies were assessed for PSMA expression and autoradiography. CB307 internalized into PSMA- and CD137-positive cells. PSMA-VH x MSA exhibited superior xenograft penetration than unbound PSMA-VH and full-length PSMA-directed antibodies. In patients, no 89Zr-CB307-related adverse events occurred. In the three patients receiving the highest protein dose (5 mg 89Zr-CB307 with 100 mg unlabeled CB307), the geometric mean 89Zr-CB307-SUVmax in all 18F-PSMA-positive lesions increased from 3.53 (day 2) to 4.12 (day 7). Highest uptake was observed in the liver (SUVmean 13.06 ± 2.68 (day 7)), with no significant uptake in the spleen, normal lymph nodes, bone marrow, or salivary glands. Tumor biopsies confirmed radioactivity. 89Zr-CB307 selectively accumulated in PSMA-positive tumor lesions without specific uptake in PSMA-positive-normal or lymphoid tissues in patients with mCRPC.

The human plasma proteome contains extensive diagnostic information but remains difficult to interrogate because protein concentrations span more than ten orders of magnitude, with highly abundant proteins such as albumin masking low-abundance biomarkers. Nanoparticle (NP) enrichment strategies partially address this limitation but remain dominated by albumin adsorption. Here we show that the nanoparticle protein corona can be rationally reprogrammed by pre-incubating plasma with a chemically diverse panel of ligands designed to (i) target specific functional sites on albumin and (ii) reduce its interactions with NPs. Molecular docking and structural analyses demonstrate that these ligands induce allosteric conformational changes and surface charge redistribution on albumin, inhibiting its association with the NP surface. Importantly, this strategy is highly tunable, as different ligands selectively enrich distinct families of low-abundance proteins within the corona. Using this approach, we quantified over 6,500 proteins from a single human plasma sample across a curated panel of conditions, substantially exceeding the depth achieved with untreated NP enrichment. These findings establish a versatile chem-bio strategy for ligand-directed protein corona engineering, enabling high-depth plasma proteome profiling and robust detection of ultra-low-abundance proteins and potential biomarkers across human diseases.

Chronic wounds, characterized by prolonged inflammation and impaired tissue regeneration, represent a critical clinical challenge, particularly in diabetic patients. Conventional therapies often fail to address the multifaceted demands of healing, which requires integrated structural support, bioactive signaling, and immune modulation. To overcome these limitations, we engineered a macroporous cryogel scaffold from methacryloyl-modified human plasma (PlasmaMA) via cryopolymerization. This process transforms the native bioactivity of plasma into a stable, biomimetic extracellular matrix (ECM)-like architecture with tunable mechanical resilience and degradability. The resulting PlasmaMA cryogel inherently retains essential human ECM proteins (e.g., albumin, fibronectin, fibrinogen) and growth factors (e.g., VEGF), which collectively facilitate robust cell adhesion, sustain pro-regenerative signaling, and promote angiogenesis. In vitro, the scaffold demonstrates potent antioxidant activity and attenuates pro-inflammatory responses in macrophages. In a diabetic rat wound model, the PlasmaMA cryogel significantly accelerated wound closure, enhanced collagen deposition and maturation, and improved functional neovascularization compared to scaffolds derived from bovine or human serum albumin. By converging native bioactivity with engineered material properties, the PlasmaMA cryogel creates a pro-healing microenvironment that actively orchestrates tissue repair. This work establishes a versatile human plasma-derived platform as a promising multifunctional therapy for complex wound healing.

Liposome stability is strongly influenced by rapid protein adsorption once they enter biological environments. This dynamic "protein corona" alters membrane properties, permeability, and circulation behaviour. The early stages of protein-liposome interactions and the specific processes involved are not often studied. Addressing this gap, we report the first application of simultaneous absorption, polarized intrinsic emission (280 nm excitation), and scattering (APIES) spectroscopy with rapid mixing to monitor in real time, with second-level resolution the interaction of Human serum albumin (HSA) with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes (Dh ∼150-160 nm) in ammonium bicarbonate buffer of varying ionic strength (25 to 150 mM). Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to measure changes in particle size distribution (PSD). APIES clearly showed a three-phase interaction process: first rapid (0-200 seconds) protein adsorption without penetration and osmotic pressure induced size decrease (∼5 to 10%); second, a penetration phase (up to ∼30 minutes) where HSA enters the lipid bilayer, and third, an annealing phase (up to 3 hours) where HSA-DMPC particle size gradually increased (by ∼2 to 5%). APIES characterized the first phase by constant absorbance (i.e. no protein loss), minimal spectral shifts, but small reductions in emission intensity and ratio of fluorescence band area to Rayleigh-Mie scatter band area (AFI/Ry). Phase two displayed constant absorbance, minimal changes in AFI/Ry, but relatively large blue shifts (indicative of tryptophan environment changes). The final phase displayed constant absorbance, gradual increase in AFI/Ry (which correlates linearly with particle size) and fluorescence intensity with minimal emission maxima changes. APIES also clearly resolved differences due to ionic strength (electrostatic screening effects) by AFI/Ry, (decreased by ∼20% at 25 mM compared to <5% at 100-150 mM after 30 minutes) hypsochromic spectral shifts (5.9 ± 1.2 nm at 25, 3.0 ± 0.8 nm at 150 mM after 3 hours). DLS confirmed that HSA-DMPC size decreased significantly within 200 seconds after mixing, and the gradual size increase afterwards. NTA confirmed the effect of ionic strength on HSA-liposome complex size and PSD. In conclusion, APIES is a powerful, yet simple tool for monitoring protein corona formation in real time (~1 s resolution), providing more detailed mechanistic insights beyond PSD changes.

Objective: To investigate the efficacy and safety of 36 000 IU recombinant human erythropoietin (rhEPO) in the treatment of cancer-related anemia (CRA) and to evaluate whether 36 000 IU rhEPO can serve as a rational "reduced-dose alternative" to the 40 000 IU rhEPO regimen. Methods: The multicenter, open-label, non-inferiority, randomized controlled trial was conducted from March 2023 to July 2024 across 12 hospitals in China, including Liaoning Cancer Hospital. A total of 119 patients with CRA were enrolled and randomly assigned to receive the 36 000 IU rhEPO (n=61) or 40 000 IU rhEPO (n=58). The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline at weeks 9-13. Secondary efficacy endpoints included hematologic and other biochemical parameters, transfusion requirements, quality of life (QOL), which was assessed by QOL scores and Karnofsky performance status (KPS) scores, and overall survival. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). Results: The least-squares mean changes in Hb from baseline to weeks 9-13 were (12.9±2.3) g/L in the 36 000 IU group and (13.4±2.4) g/L in the 40 000 IU group. Analysis of covariance showed no statistically significant difference between groups (F=-0.21, P=0.836), with a between-group difference of (-0.5±2.5) g/L (95% CI: -5.4 g/L, 4.4 g/L). The lower limit of the 95% CI (-5.4 g/L) exceeded the predefined non-inferiority margin of -10 g/L, indicating non-inferiority of the 36 000 IU dose compared to the 40 000 IU. At week 13, the proportions of patients with Hb increase ≥10 g/L were 82.0% (50/61) in the 36 000 IU group and 86.2% (50/58) in the 40 000 IU group, with no significant difference between groups (Qmh=0.40, P=0.527). The average weekly transfusion rate was 2.0% in both groups. No significantly significant differences were observed between the two groups in terms of changes in hematocrit, reticulocyte percentage, folate, vitamin B12, albumin, iron metabolism markers, QOL scores, KPS scores, or overall survival (all P＞0.05). Regarding safety, the incidence of TEAE was 80.3% (49/61) in the 36 000 IU group and 84.5% (49/58) in the 40 000 IU group, with nausea, fever, and fatigue being the most common symptoms (incidence＞5%). No drug-related serious adverse events were reported, and there were no significant differences between the groups (P＞0.05). Conclusions: The 36 000 IU dose of rhEPO is non-inferior to the 40 000 IU dose in terms of efficacy and has a favorable safety profile for the treatment of CRA. These findings support the use of 36 000 IU rhEPO as a reasonable clinical option for managing CRA.