Bio-based pyrrolidone diacids serve as the core site to facilitate substrate–enzyme binding, realizing the eco-friendly recycling of PE-like polyesters via commercial enzymes.

Activation of CD40, a pivotal component of immune oncology, could facilitate the infiltration of immune cells into the tumor microenvironment. In this investigation, we characterized SHR-2005, a second-generation CD40 agonistic mAb, as a potential candidate for cancer immune therapy. Our results showed that SHR-2005 possessed high affinity in binding to both human and rhesus CD40 and could effectively compete with CD40L for CD40 binding. Notably, SHR-2005 was engineered to exert a strong affinity for human FcγRIIb, consistent with its observed Fc receptor–dependent agonistic activity. Treatment with SHR-2005 led to robust activation of the CD40 signaling pathway and subsequent immune response. The murine surrogate SHR-2005–mIgG1 exhibited potent inhibition of tumor growth in the MC38 allograft model and showed enhanced antitumor efficacy in combination with the anti–PD-L1 antibody. Furthermore, intravesical instillation of SHR-2005–mIgG1 also increased the populations of dendritic cells (DC), CD3+ T cells, and CD4+ T cells in bladder tissue. No obvious abnormality except for a reversible local irritation was observed via intravesical instillation. Notably, SHR-2005 induced significantly lower IL-6 secretion than the APX005M analogue in human peripheral blood mononuclear cells, indicating a favorable safety profile. In conclusion, the CD40 agonistic antibody SHR-2005 was highly reliant on FcγR for agonistic activation and exhibited promising potential for clinical development as monotherapy or in combination with the anti–PD-L1 antibody for the treatment of solid tumors. Based on promising efficacy and tolerance in preclinical studies, SHR-2005 is currently being evaluated in an ongoing phase I clinical trial for the intravesical treatment of high-risk non–muscle-invasive bladder cancer.

CycDiff-DPO uses preference-aligned diffusion to design target-specific macrocyclic peptides with enhanced membrane permeability, balancing binding competence and cell permeability in one framework.

Poly(ethylene terephthalate) (PET) hydrolases have emerged as promising biocatalysts for closed-loop plastic recycling. Among the most efficient enzymes reported to date, LCC-ICCG exhibits exceptional PET-depolymerization performance under industrially relevant conditions. However, the molecular basis for its superior activity relative to engineered PETases such as FAST-PETase and HotPETase remains incompletely understood. Here, we combine microsecond-scale molecular dynamics simulations, quantum mechanical cluster calculations, pre-reaction-state analysis, noncovalent-interaction mapping, and distortion/interaction activation strain analysis to compare LCC-ICCG with FAST-PETase and HotPETase. The simulations show that LCC-ICCG samples catalytically competent pre-reaction-state geometries more frequently, mainly because V212 reshapes the local environment around the scissile ester. This residue relieves steric congestion, supports weak C–H···O guided substrate preorganization, and reinforces both the Asp-His catalytic dyad and the W190-associated pocket architecture. Density functional theory calculations further indicate that this preorganized active site lowers the acylation barrier to 15.5 kcal/mol by reducing substrate distortion and strengthening transition-state interactions. High-temperature simulations show that LCC-ICCG better preserves near-attack geometries at 350 K, linking thermal robustness to sustained catalytic preorganization. Moreover, reciprocal I208V mutations in IsPETase-derived enzymes enrich pre-reaction-state populations, supporting the transferability of the V212-centered design principle. Overall, these results establish pre-reaction-state stabilization as a key determinant of PET-hydrolase efficiency and provide mechanistic design rules for engineering next-generation PET depolymerases.