Acta Pharmaceutica Sinica B

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Harnessing the spleen-brain axis: Magnolol-loaded nanomedicine attenuates ischemic stroke via oxidative stress mitigation and monocyte/macrophage reprogramming

Acta Pharmaceutica Sinica B. 2026, 16(7): 4634-4653.

Cerebral ischemia-reperfusion (I/R) injury is exacerbated by the infiltration of splenic monocytes/macrophages (Mo/Mϕ) via the spleen-brain axis, where splenic-derived Mo/Mϕ migrate to cerebral lesions through C-C chemokine ligand 2/receptor 2 (CCL2/CCR2) chemotaxis, thereby amplifying oxidative stress and the neuroinflammatory cascade. Building on this endogenous pathway, we devised a delivery strategy that utilizes splenic Mo/Mϕ as “living vehicles” for targeted drug delivery. To this end, we developed a spleen-targeted magnolol liposome (Mag-PEG₅K) through optimized PEGylation, ensuring its spleen-specific accumulation and uptake by splenic Mo/Mϕ. After cerebral I/R injury, these nanoparticle-laden cells migrate to the ischemic brain via the CCR2/CCL2 axis to remodel the immunomodulatory microenvironment. This targeted system orchestrates dual therapeutic mechanisms within the lesion: mitochondria-directed reactive oxygen species (ROS) scavenging mitigates oxidative stress and peroxisome proliferator-activated receptor gamma (PPARγ) activation reprograms macrophage polarization, suppressing pro-inflammatory M1 differentiation and curtailing tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) secretion. The attenuated cytokine release suppresses neuronal inflammatory cascades, thereby reducing apoptosis. In vivo, Mag-PEG₅K showed superior efficacy to free magnolol, effectively reducing infarct volume and improving long-term neurological outcomes. Supported by favorable biosafety, this work proposes spleen-targeted nanotherapy as an innovative strategy for reprogramming peripheral immunity via the spleen-brain axis, highlighting the translational potential of Mag-PEG₅K for addressing neuroinflammation and oxidative damage in ischemic stroke.
Enhanced tumor immunotherapy by nanovesicles derived from engineered DC-like M1 macrophage

Acta Pharmaceutica Sinica B. 2026, 16(7): 4654-4675.

To explore a therapeutic approach with dual functions of activating cytotoxic CD8⁺ T cells and remodeling immunosuppressive tumor-associated macrophages (TAMs), the engineered macrophage-derived nanovesicles (MAC-PNV) were developed in this study. The MAC-PNV were derived from activated DC-like M1 macrophages after reprogramming macrophages by transcription factors PIB (PU.1, IRF8, and BATF3) and further stimulated with antigenic peptide, lipopolysaccharide (LPS), and interferon-γ (IFN-γ). In vitro results demonstrated that the enriched antigen-presenting complexes and co-stimulatory molecules were displayed on the surface of pro-inflammatory cargo-contained MAC-PNV, which enabled significant activation of CD8⁺ T cells and repolarization of M2 macrophages towards the M1 phenotype. After peritumoral administration, MAC-PNV alone significantly inhibited tumor growth by promoting the activation and intra-tumoral infiltration of CD8⁺ T cells, and remodeling the immunosuppressive tumor microenvironment (TME) in B16-OVA-bearing mouse models. More importantly, MAC-PNV remarkably enhanced the anti-tumor efficacy of low-dose liposomal doxorubicin (DOX-Lipo, 1 mg/kg), along with reducing its dose-limiting toxicities in B16-F10-bearing mouse models. This study highlights that the MAC-PNV would be a potential and effective immunomodulatory enhancer for providing a promising combination strategy with clinical chemotherapeutics.
In situ generation of EBNA1 CAR-T cells eradicates antigen specific auto-immune B cells for multiple sclerosis treatment

Acta Pharmaceutica Sinica B. 2026, 16(7): 4676-4691.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Epstein-Barr virus (EBV)-induced B-cell overactivation could lead to inflammatory injury to the CNS, which is thought to underlie the initiation and progression of MS. To specifically eradicate these B cells, we report in situ EBNA1-specific chimeric antigen receptor (CAR)-T cells that were transiently programmed with circular RNA (circRNA)-laden CD7-targeted lipid nanoparticles (CD7-LNP). We demonstrate that systematic injection of CD7-LNP can efficiently introduce CAR circRNA to T lymphocytes and yield in vivo CAR-T cells. These in situ CAR-T cells were able to specifically clear EBNA1-specific B cells and significantly mitigate the progression of MS in a MS mouse model. Thus, in situ generation of EBNA1-specific CAR-T cells hold promise as a therapeutic strategy for MS that avoids the risks of general immunosuppression, and warrant further clinical trials.
Target degradation of CASPASE-1 for alleviation of inflammation in sepsis via optogenetically engineered extracellular vesicles

Acta Pharmaceutica Sinica B. 2026, 16(7): 4692-4705.

Sepsis is a comprehensive ailment of systemic inflammatory response syndrome arising from infection. Activation of CASPASE-1 plays a central role in initiating the inflammatory cascade during sepsis. Herein, we construct optogenetically engineered extracellular vesicles (EVs) that achieve the specific degradation of CASPASE-1 and inhibit sepsis-associated inflammation. Specifically, blue light (460 nm)-induced CRY2/CIBN heterodimerization was applied during the EVs production stage to selectively load GCE-CTM fusion proteins into EVs by EXPLORs technology, yielding EVsGCE⁻CTM loading efficiency compared to conventional methods. Upon systemic delivery, EVsGCE⁻CTM preferentially accumulated in macrophages, where the GCE domain selectively bound activated CASPASE-1. The CTM motif then facilitated its lysosomal degradation by chaperone-mediated autophagy, resulting in potent inhibition of CASPASE-1 activity. In a murine model of sepsis, treatment with EVsGCE⁻CTM effectively attenuated systemic inflammation, reduced multi-organ damage, and significantly improved survival outcomes. This approach enables highly efficient, ubiquitin-independent degradation of intracellular target proteins through macrophage-directed EVs delivery, offering a potential therapeutic approach to address sepsis and other inflammation-related diseases.
Bladder adaptive hydrogel scaffold with dual release, antimicrobial, immunomodulatory, and repair: DRIVER for urinary tract infections

Acta Pharmaceutica Sinica B. 2026, 16(7): 4706-4724.

Urinary tract infections (UTIs), especially complex or recurrent cases, present a significant challenge. Systemic antibiotics often fail to provide adequate local drug concentrations, leading to limited efficacy and relapse. Local delivery is hindered by the bladder’s dynamic environment, causing rapid drug clearance. To address this, a hydrogel scaffold, DRIVER (dual release, repair of tissues, immunomodulation, vesical adaptation, elimination of pathogens, and regulation of autophagy), is designed for sustained release in sync with the infection cycle. DRIVER forms a self-regulating 3D network through dynamic bonding and metal ion coordination, ensuring stable release and adaptability. It delivers a biphasic release profile comprising an initial antimicrobial burst that rapidly suppresses acute infection, followed by a 7-day sustained release phase. In vitro, DRIVER retained potent antibacterial and antifungal activity against planktonic, biofilm-embedded, and intracellular pathogens, including drug-resistant strains. Notably, the hydrogel also promoted bladder and kidney repair by modulating mitochondrial activity and autophagy, pathways essential for restoring urothelial integrity. DRIVER achieved >3 log reductions in bacterial and fungal burdens, normalized urinary function, and markedly attenuated systemic and tissue inflammation. Histological analyses confirmed robust architectural recovery in both the bladder and kidney. Together, these findings establish DRIVER as a compelling therapeutic strategy for complex UTIs.
Dual-pathway induction of pyroptosis via biomineralized-like nanoparticles trigger potent immunotherapy against tumor

Acta Pharmaceutica Sinica B. 2026, 16(7): 4725-4738.

Pyroptosis, a highly pro-inflammatory form of immunogenic cell death, holds great promise for cancer treatment. However, its efficacy in cancer cells is often limited due to low efficiency and cellular complex pro-survival mechanisms. In this study, we address this challenge by an integrated nanoplatform simultaneously activating two pathways of pyroptosis. Manganese ions and imidazole serve as a framework to coordinate glucose oxidase (GOx) and epigallocatechin gallate (EGCG) into stable biomineralized-like nanoparticles. We hypothesize that EGCG, as an inhibitor of DNA methyltransferase, may restore the expression of Gasdermin E (GSDME), a crucial component of pyroptosis activated by cleaved caspase-3. Through glucose consumption, GOx triggers both the caspase-1/Gasdermin D (GSDMD)-mediated and caspase-3/GSDME-mediated pathways of pyroptosis simultaneously, leading to efficient pyroptosis in cancer cells and a robust anti-tumor immune response, accompanied by the upregulated expression of PD-L1. Our results reveal that integrating this strategy with immune checkpoint inhibitors results in a tumor inhibition rate exceeding 80% across several “cold” tumor models, a 20% cure rate in the CT26 unilateral tumor model, and 5/8 distant tumors remaining free of recurrence upon re-challenge. In conclusion, this dual-pathway induction of pyroptosis offers a novel and promising strategy for enhancing cancer immunotherapy.
Cryptic pockets in proteins: Harnessing conformational dynamics for rational drug design

Acta Pharmaceutica Sinica B. 2026, 16(7): 4739-4742.
Reaction-aware molecular representation learning: Toward generalizable artificial intelligence for enzymatic catalysis

Kelin Xia

Acta Pharmaceutica Sinica B. 2026, 16(7): 4743-4745.
Reprogramming the spleen-brain axis: Splenic monocyte/macrophage-mediated nanotherapy for ischemic stroke

Acta Pharmaceutica Sinica B. 2026, 16(7): 4746-4747.
Recent advances in antiviral drugs for Chikungunya virus (CHIKV): Targets, mechanisms, and development strategies

Xiaowen Jiang, Yudan Zhao, Hongyuan Lu, Keqiang Li, Huiyuan Gao

Acta Pharmaceutica Sinica B. 2026, 16(6): 3257-3291.

Chikungunya virus (CHIKV), an alphavirus transmitted by Aedes mosquitoes, has frequently caused outbreaks in tropical and subtropical regions worldwide, posing a significant public health threat. CHIKV infection leads to chikungunya fever, characterized by fever, rash, and persistent joint pain, with approximately 30%-40% of patients developing chronic arthritis that severely impacts quality of life. Currently, no specific antiviral drugs or vaccines against CHIKV have been approved for clinical use, highlighting the urgency of drug development. This review systematically summarizes recent progress in antiviral research on CHIKV, focusing on key target proteins in the viral life cycle, such as non-structural proteins nsP1, nsP2, nsP3, nsP4, and structural protein E1-E2 complexes, as well as the mechanisms of action of their inhibitors. We analyze the current research status of various anti-CHIKV compounds, including suramin, baicalin, halofuginone, betulinic acid, andrographolide, and itraconazole. Additionally, we summarize host-directed antiviral strategies targeting pathways such as host cell oxidative folding, Na⁺/K⁺-ATPase, and MAPK signaling. This review aims to establish a theoretical foundation and outline potential research directions for the development of CHIKV-related therapeutics, thereby facilitating the discovery of effective treatment strategies against this pathogen.

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