Acta Pharmaceutica Sinica B

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A triple combination strategy for nasopharyngeal carcinoma: Aptamer-guided liposomal chemotherapy, engineered NK cells, and Fc-enhanced PD-L1 antibody therapy

Acta Pharmaceutica Sinica B. 2026, 16(3): 1584-1604.

The effective treatment of nasopharyngeal carcinoma (NPC) is challenged by an immunosuppressive tumor microenvironment (TME) and insufficient immune effector cell activation. Herein, we design a synergistic tri-modal therapeutic strategy to overcome these barriers. This platform integrates: (1) a CD109-targeted liposomal doxorubicin (S3-Lip-DOX) for precise chemotherapy and induction of immunogenic cell death (ICD); (2) non-genetically engineered natural killer (NK) cells armed with dual aptamers (targeting CD109 and PD-L1) via bio-orthogonal chemistry for enhanced tumor recognition (S3-P-NK); and (3) an Fc-engineered anti-PD-L1 antibody (Atezolizumab/IgG1) that restores antibody-dependent cellular cytotoxicity (ADCC). Crucially, we uncovered a key mechanistic synergy: S3-Lip-DOX treatment, as a stress-adaptive response, upregulates PD-L1 expression on NPC cells. This finding provides a compelling rationale for the integration, turning a potential immune escape mechanism into a therapeutic vulnerability. The complete regimen, comprising S3-Lip-DOX, S3-P-NK, and Atezolizumab/IgG1, demonstrated potent synergistic antitumor effects in vitro and in vivo. This triple-combination therapy not only achieved significant tumor regression but also robustly reprogrammed the innate tumor microenvironment, evidenced by enhanced dendritic cell (DC) maturation and pro-inflammatory macrophage activation. This work establishes a mechanism-driven, modular therapeutic platform that effectively coordinates targeted chemotherapy with innate immunotherapy, holding significant translational potential for solid tumors.
Dichotomous role of CD47-SIRPα axis: Leveraging opposing functions in phagocytic resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration

Acta Pharmaceutica Sinica B. 2026, 16(3): 1605-1624.

Polyethylene glycol (PEG) carriers can improve drug circulation, but encounter biocompatibility and tumor penetration challenges. The CD47-SIRPα interaction on macrophages can initiate a “don't-eat-me” signal, inhibiting phagocytosis. This study elucidates the dichotomous role of the CD47-SIRPα axis in conferring phagocytosis resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration. Using CD47-functional peptide, we elucidated the capacity of this axis to preserve carrier-cell membrane accessibility, impede macrophage-mediated nanocarrier endocytosis, reduce the secretion of IgG and IgM antibodies, and attenuate complement cascade activation. These mechanisms collectively neutralize the accelerated blood clearance of PEGylated liposomes. Notably, we identified the presence of SIRPα in endothelial vasculature and, for the first time, verified its pivotal role in orchestrating liposomal transit across the endothelial barrier. Moreover, within the tumor region, the CD47-SIRPα axis facilitated carrier hitchhiking on macrophages, enabling deep penetration into the tumor parenchyma and regulating the tumor microenvironment through the differential recognition of M1/M2-type tumor-associated macrophages. This study presents the first evidence of the dichotomous role of the CD47-SIRPα axis in regulating carrier biocompatibility, offering insights into its function to overcome the tumor permeability barrier challenge.
Liposomal simvastatin potentiates intranasal H1N1 influenza subunit vaccine via increasing transcytosis of antigen and submucosal dendritic cell recruitment

Afeng Yang, Chen Zhang, Aihua Wu, Jiaojiao Xu, Hongzheng Lin, Zhe Li, Tingting Li, Yunlu Li, Ningshao Xia, Xunlong Shi, Tianying Zhang, Wei Lu

Acta Pharmaceutica Sinica B. 2026, 16(3): 1625-1642.

Intranasal vaccines specifically eliciting mucosal immunity in the upper respiratory tract have shown advantages in protecting against respiratory virus invasion. Yet, no clinically licensed intranasal adjuvant remains a major hurdle for the development of intranasal vaccines with low immunogenic antigens like subunit vaccines. Here, we show that liposomes loading simvastatin (Lipo-SV) serve as potent mucosal adjuvants for the intranasal liposomal subunit vaccine encapsulating the hemagglutinin 1 (HA1) glycoprotein of A/PR/8/34 (PR8) H1N1 influenza (Lipo-HA1), providing robust protection against the lethal PR8 H1N1 infection. Compared to cholera toxin subunit B (CTB), the only mucosal adjuvant used in humans, the Lipo-SV substantiate intranasal Lipo-HA1 vaccines to elicit robust systemic and local mucosal immune responses. The underlying mechanism of the adjuvanticity of Lipo-SV involves the increased transcytosis of antigens by inhibiting the geranylgeranylation of RAB5 and RAB7B GTPases in nasal epithelial cells. Moreover, Lipo-SV enhance the submucosal recruitment of dendritic cell for antigen uptake via the Toll-like receptor 4-dependent pathway. Unlike CTB, intranasal Lipo-SV do not induce inflammation in the lung or the inflammatory cytokines in the central nervous system. Our results present a paradigm of design of mucosal adjuvant to target the mucosal epithelial cells in addition to the antigen-presenting cells.
Multivalent sulphur-modified biosilica nanostructures for bacterial enteritis therapy

Acta Pharmaceutica Sinica B. 2026, 16(3): 1643-1661.

Bacterial enteritis is a specific gastrointestinal tract disorder caused by pathogenic bacterial infection, which not only disrupts the commensal microbiota but also contributes to cascaded complications. Here, we prepared polyethyleneimine (PEI)-based mesoporous silica nanostructures, co-modified with -SH and -S-S- groups, to simultaneously eradicate the pathogenic bacteria, regulate the immune response, and reprogram the inflammatory microenvironment in the infected intestine. Referring to the multivalent sulfur modification, the -S-S- group, with its oxidizability, perturbs the glutathione balance within bacteria, while the combined reductive capacity of -SH and -S-S- scavenges excessive reactive oxygen species and mitigates inflammation-induced damage. Additionally, the well-developed nanopores with a positively charged PEI network facilitate the absorption of bacterial lipopolysaccharide, lipopeptides, flagella and cell-free DNA through hydrogen bonding and electrostatic interactions. Furthermore, the biosilica nanostructures enable the efficient encapsulation of conventional antibacterial agents, such as berberine chloride and norfloxacin, thereby achieving targeted delivery and reducing side effects, which represents a promising strategy for next-generation antimicrobial therapies.
Heterocyclic modified paclitaxel prodrug nanoassemblies for stimuli-responsive delivery via lysosomal escape

Acta Pharmaceutica Sinica B. 2026, 16(3): 1662-1675.

Prodrug nanoassemblies offer an innovative approach to drug delivery, but their lysosomal entrapment often impairs drug release. Notably, tertiary amine structures can undergo protonation reactions, thereby facilitating lysosomal escape through the proton sponge effect. In this study, we developed three novel paclitaxel prodrug nanoassemblies (PTX-SS-NO NPs, PTX-SS-CC NPs and PTX-SS-NC NPs) featuring distinct heterocyclic tertiary amine structures to investigate structure-activity relationships in lysosomal escape and drug delivery. Among them, PTX-SS-NC NPs demonstrated excellent lysosomal escape capability, enabling rapid drug release into the cytosol. Systematic evaluation revealed that the PTX-SS-NC NPs exhibited optimized pharmacokinetics and significant tumor accumulation, further contributing to their strong antitumor efficacy. Our findings establish heterocyclic tertiary amines as crucial design elements for overcoming lysosomal entrapment and optimizing chemotherapeutic prodrug nanoassemblies.
Reversibly unlocking the blood-brain barrier: A study on microtubule dynamics modulation using gold nanoparticle-modified reduced graphene oxide

Junrong Wu, Guangman Cui, Zhousheng Lin, Wanmei Lin, Yaqing Zhang, Tianhang Zhou, Ping He, Yunjiao Zhang, Guangyu Yao

Acta Pharmaceutica Sinica B. 2026, 16(3): 1676-1695.

The blood-brain barrier (BBB) is a crucial biological interface between the central nervous system and circulation, playing a key role in maintaining the brain's homeostasis and function, but presenting a challenge for drug delivery. Although enhancing the paracellular permeability of the BBB using graphene-based materials (GBMs) is a promising strategy, detailed biological effects and molecular mechanisms remain poorly understood and understudied. In this study, we prepared gold nanoparticle-modified reduced graphene oxide (Au-rGO) sheets as representative GBMs to enhance BBB paracellular permeability transiently. Remarkably, the induced permeability modulation exhibited both significant efficacy and complete reversibility. Biological experiments and molecular dynamics simulations provided full insights into the molecular mechanism of this process, confirming that Au-rGO influences the dynamic equilibrium of MTs by adsorbing soluble tubulins to hinder MT polymerization, and disassembling MTs to promote depolymerization, thus mediating the unlocking of the BBB. Moreover, the subsequent closure of the BBB is mediated by increased MT polymerization, regulated by the activation of the ERK-stathmin pathway. Collectively, this present study comprehensively elucidates the phenomenon of reversible BBB opening induced by Au-rGO and its intricate molecular mechanism, and supports the safety and efficacy of Au-rGO as a paracellular penetration enhancer for enhancing BBB drug delivery efficiency.
Extracellular vesicles-derived hybrid biomimetic nanoplatforms camouflaged Golgi apparatus-targeted aggregation induced emission photosensitizer to elicit pyroptosis and immunogenic cell death for efficient antitumor photoimmunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(3): 1696-1716.

Pyroptosis is a unique programmed cell death pattern, and targeting it is an effective strategy against cancer therapy by overcoming apoptosis resistance. However, Golgi apparatus-targeted aggregation induced emission (AIE) photosensitizer as pyroptosis inducer for efficient antitumor treatment has not been reported. In this study, we successfully synthesized three new AIEgens, including TMN, TBN and TCN, by changing functional groups through a reasonable molecular design strategy, which targeted mitochondria, lysosome and Golgi apparatus (GA), respectively. In vitro experiments demonstrated that TCN exhibited the strongest reactive oxygen species (ROS) production ability and significant phototoxicity. Therefore, TCN as the GA-targeted AIE photosensitizer wore biomimetic hybrid extracellular vehicles (EVs) and M1-type macrophage membranes (denoted as EM@TCN) as pyroptosis inducer were rationally designed and engineered to trigger the production of GA cytotoxic ROS in situ. EM@TCN plus white light irradiation caused GA oxidative stress and induced pyroptosis synergistic photoimmunotherapeutic, which could rebuild tumor microenvironment and improve tumor immunogenicity. Combined with αPD-L1 (anti-mouse PD-L1 antibody), the biomimetic hybrid delivery system EM@TCN significantly inhibit the both primary and distant tumors, and effectively suppress the orthotopic breast tumor. This is the first report on a hybrid nanovesicle coated GA-targeted AIE photosensitizer to induce pyroptosis for combination with αPD-L1 to enhance antitumor photoimmunotherapy.
Exploiting eNOS activation to achieve tumor vascular normalization via endothelial transcytosis of lipid nanoparticles

Acta Pharmaceutica Sinica B. 2026, 16(3): 1717-1732.

Abnormal tumor vasculature greatly accelerates tumor progression and diminishes antitumor treatments. Restoring perivascular NO gradients is available to maintain tumor vessel homeostasis and promote tumor vascular normalization. However, exogenously delivering NO strategies lacks the durability to maintain precise NO localization around tumor vessels. Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO₂ into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies. The Ca²⁺ and Met released in ECs could restore perivascular localization of NO by activating endothelial NOS (eNOS). Additionally, MC@L internalized by tumor cells could cause CaO₂-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O₂ generation and H⁺ consumption during CaO₂ degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.
Ferroptosis-based nano-assembly enhanced breast cancer therapy by inhibiting intratumor bacteria

Acta Pharmaceutica Sinica B. 2026, 16(3): 1733-1746.

Intratumoral bacteria, especially Gram-positive bacteria (G⁺), have a unique bacterial niche in breast cancer that promoted tumor progression. However, the effects of G⁺ have so far been overlooked, serving an “invisible driver” of breast cancer. Moreover, due to the altered biological structure of G⁺ in tumor cells and the penetration barrier of antibiotics, the effect of antibiotic-mediated eradication of G⁺ in tumors is limited. Here, to simultaneously inhibit intratumoral G⁺ and tumor cells via ferroptosis therapy, an amorphous nano-assembly (DFTV) was constructed by assembling doxorubicin (DOX), tannic acid (TA), FeSO₄, and vancomycin (Van). DFTV treatment effectively targets intratumoral G⁺, thereby inhibiting the growth of the breast tumor and postoperative recurrence by downregulating the expression of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Moreover, inhibiting intracellular G⁺ also restrains the reorganization of F-actin to form pseudopodia, thereby impairing tumor cell motility and blocking metastasis. Collectively, DFTV improves the antitumor efficacy by targeting G⁺ in breast tumors, offering novel insights into overcoming the limitations associated with the lack of intratumoral antibacterial therapy in clinical breast cancer treatment protocols.
bHLH130 mediates gibberellin signaling to regulate tanshinone biosynthesis in Salvia miltiorrhiza

Acta Pharmaceutica Sinica B. 2026, 16(3): 1747-1761.

Salvia miltiorrhiza is a prominent traditional Chinese medicinal (TCM) herb with notable therapeutic applications, especially in treatment of cardiovascular and cerebrovascular diseases. A crucial role in promoting tanshinone biosynthesis is attributed to the gibberellic acid (GA) signaling pathway; however, its precise regulatory mechanisms remain incompletely understood. In the current investigation, we identified bHLH130, a GA-responsive bHLH transcription factor (TF), via transcriptomic analysis of GA-treated hairy roots from S. miltiorrhiza. Functional analysis demonstrated that bHLH130 overexpression markedly suppressed tanshinone biosynthesis, whereas its knockout resulted in elevated tanshinone accumulation. Additionally, it was confirmed that bHLH130 directly targets E-box motifs within the promoters of biosynthetic genes, including DXS2, CPS1, KSL1, and CYP76AH1, thereby negatively regulating their transcriptional activities. Moreover, bHLH130 interacts with DELLA4, forming a regulatory complex implicated in the modulation of tanshinone biosynthesis. Co-overexpression assays revealed that DELLA4 attenuated the inhibitory effects of bHLH130 on tanshinone accumulation. Collectively, our data propose that the bHLH130-DELLA4 interaction constitutes a critical regulatory node, balancing GA signaling with secondary metabolite production and offering novel strategies for the metabolic engineering of tanshinones. In conclusion, this research delineates the regulatory role of bHLH130 in tanshinone synthesis, providing valuable insights into the GA-mediated modulation of secondary metabolism.

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