Acta Pharmaceutica Sinica B

An immunostimulant nanomedicine enhances radioimmunotherapy by remodeling the tumor immunosuppressive landscape after radiotherapy

Mengwan Jiang, Mingyue Chen, Wen Zou, Yingxin Xie, Jinjin Shi, Junjie Liu, Aibing Chen, Xiu Zhao

Acta Pharmaceutica Sinica B. 2026, 16(2): 1059-1073.

Studies have shown that radiotherapy (RT) has powerful immune-stimulating effects. However, RT-mediated distal tumor regression is rare in clinical practice. Here, with an animal experimental model, we found that RT shaped an immunosuppressive landscape characterized by a high-influx of myeloid-derived suppressor cells (MDSCs), and the induction of immunologically silent tumor apoptosis, hindering the efficacy of radioimmunotherapy. To address this issue, we developed a spatiotemporally controlled nanomedicine for remodeling the immunosuppressive tumor microenvironment (TME) post-RT. Decitabine (DAC)-loaded ferritin (Ft) were crosslinked via an azobenzene linker, and meanwhile encapsulated with all-trans retinoic acid (ATRA) to construct a Ft@DAC@ATRA nanoassembly (denoted as FD@ATRA), which dissociated into monodispersive Ft@DAC units in hypoxia TME. The released ATRA could eliminate immunosuppressive MDSCs, and meanwhile Ft@DAC selectively induced immunogenic pyroptosis of the tumor by targeting the transferrin receptor 1 overexpressed on the tumor to effectively activate CD8⁺ T cells. FD@ATRA treatment reshaped the tumor immune landscape post-RT with an increase of 16.8% in tumor-infiltrating IFN-γ⁺CD8⁺ T cells. Moreover, FD@ATRA-enhanced RT remained effective in large, treatment-resistant tumors, and the inhibition rate of FD@ATRA-enhanced RT on distant tumors improved by 47% compared to the RT group alone, providing an effective therapeutic approach to improve the clinical outcomes of radioimmunotherapy.

Cold exposure-induced β-hydroxybutyrate promotes brown fat mitochondrial lipid droplet contact to ameliorate fatty dysfunction and hepatic steatosis

Acta Pharmaceutica Sinica B. 2026, 16(2): 930-947.

Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived β-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.

Multifunctional extracellular vesicles inhibiting autophagy ameliorate immunotherapy in non-small cell lung cancer

Acta Pharmaceutica Sinica B. 2026, 16(2): 1022-1045.

The modulation of tumor autophagy to enhance antitumor immunity has garnered significant attention, underscoring its critical role in cancer immunotherapy. However, advanced strategies for precise autophagy-regulating drug delivery remain a pressing need. Here, we introduce a targeted small extracellular vesicles (sEVs)-based drug delivery system capable of simultaneously loading antibodies and nucleic acid drugs while ensuring their accurate release in the tumor microenvironment (TME). We developed a dual-stimulation electroporation system that integrates nanosecond electric pulses and ultrasound to enhance sEV production, yielding IL-7 mRNA-enriched sEVs that overexpress CD64 receptors for efficient capture of anti-PD-L1 antibodies. These multifunctional autophagy-inhibiting and immunomodulatory sEVs (AI-sEVs) are designed to inhibit autophagy and modulate immune responses in non-small cell lung cancer. Upon delivery to the TME, AI-sEVs mediate the enzymatic cleavage of peptide bonds, releasing IL-7 mRNA. This process induces autophagy suppression and restores MHC-I expression, which synergizes with anti-PD-L1 immune checkpoint inhibition to enhance antitumor efficacy. In conclusion, this study proposes an innovative methodology that utilizes engineered sEVs for the co-delivery of protein antibodies and genetic materials. This approach establishes a promising strategy for advancing cancer immunotherapy by targeting the modulation of autophagy.

Biomimetic nitric oxide nanogenerators for synergistic gas-mild photothermal therapy of large solid tumor

Caixia Tan, Ming Yan, Xinping Luo, Honghao Sun, Zhanwei Zhou, Minjie Sun

Acta Pharmaceutica Sinica B. 2026, 16(2): 1074-1089.

The mild photothermal therapy of solid tumors was still bottlenecked by the uneven temperature distribution in tumor tissue and the autophagy-mediated resistance. Here, we leveraged the ultra-small size (approximately 0.32 nm) and autophagy inhibitory property of nitric oxide (NO) to overcome these limitations for enhanced gas-photothermal therapy of large tumors. An NO donor was loaded into mesoporous polydopamine and coated with tumor cell membranes for tumor-targeting delivery. The acid-triggered release of NO potently inhibited autophagy to block the pro-survival pathway of tumor cells. Besides, as a small-molecule gas, it diffused freely into deep regions and precisely eliminated the deep-seated tumor cells, resulting in approximately 90% tumor inhibition in the late-stage breast tumor model (>500 mm³). The NO gas therapy shows great potential for complementing other therapeutics for the synergistic therapy of large solid tumors.

Intratumoral immune-microbial crosstalk shaped by tumor cell-derived extracellular vesicles encapsulating berberine boosts lung cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(2): 1090-1115.

The intratumoral microbiome plays a crucial role in cancer progression, prompting the development of therapies targeting it. However, due to the heterogeneous effects of intratumoral microbes, designing treatments tailored to the unique microecological characteristics of individual tumors poses a significant challenge. Here, we found significant variations in the abundance of five bacterial genera—Lysinibacillus, Stenotrophomonas, Weissella, Comamonas, and Aeromonas—between lung adenocarcinoma (LUAD) and normal tissues by analyzing single-cell transcriptomic datasets. These specific bacterial clusters were significantly associated with immune infiltrates in the tumor microenvironment (TME). After confirming their effects in mouse models, these bacterial taxa were identified as potential therapeutic targets. Through in vitro drug screening assays, berberine was identified as a promising agent that selectively inhibits harmful bacteria while sparing beneficial ones. To address berberine’s low solubility and tumor targeting issues, it was encapsulated into tumor cell-derived extracellular vesicles (EV-ber). Feature analysis demonstrated that EV-ber shifted the intratumoral microbiome profile toward an anti-tumor phenotype and enhanced anti-tumor immunity in the TME. Furthermore, EV-ber administration inhibited LUAD growth, impaired LUAD metastatic ability, and boosted the effectiveness of anti-PD-L1 immunotherapy in mouse models. In conclusion, this work demonstrates the potential of personalized intratumoral microbial re-education strategies in LUAD therapy.

A systemic immunogenic reactor leveraging modified γ-cyclodextrins for photo-controlled cancer Ca²⁺ interference via modulating MICU1

Qian Jing, Mengnan Zhao, Yan Tang, Tao Chen, Mingyan Sun, Dandan Mi, Lan Zou, Rujing Wang, Jun Lu, Sanjun Shi

Acta Pharmaceutica Sinica B. 2026, 16(2): 1116-1139.

Interference with calcium homeostasis provokes tumor cell death and immune response, providing a novel direction for tumor immunotherapy as a promising cancer treatment strategy. Nevertheless, most reported Ca²⁺-overloaded nanoinducers encounter challenges such as intricate preparation procedures, safety concerns arising from inorganic material input, and limited anti-tumor efficiency. Herein, we synthesized a biocompatible and pH-sensitive Ca-doped cyclodextrin metal-organic framework (Ca/K-MOF) as a carrier, which was then loaded with photosensitizer hypericin (HY) via a simple one-pot synthesis to form HY@Ca/K-MOF. To enhance the stability both in vitro and in vivo, we coated HY@Ca/K-MOF with a hydrophilic layer of PEG (PEGHY@Ca/K-MOF). When exposed to 590 nm photoirradiation, PEGHY@Ca/K-MOF, with its pH-responsive dissociation, the Ca²⁺ and HY mediators released at the tumor site share the responsibility of triggering intracellular Ca²⁺ disturbances, which amplified the production of reactive oxygen species (ROS) and led to mitochondrial calcium overload through modulating mitochondrial MICU1 function. Under photocontrol, this interplay between ROS generation and mitochondrial calcium overload created a bidirectional amplification effect, where each process reinforced the other, subsequently eliciting a pyroptosis-evoked immune response. Significantly, this newly constructed delivery platform effectively suppressed both primary and distant tumors without the need for additional immunological interventions. In summary, this Ca²⁺-doped MOF-based nanomaterial provides a promising approach for efficient tumor photo-controlled mitochondrial Ca²⁺ overload-pyroptosis immunotherapy.

Antibody-drug conjugates with DHODH inhibitor as novel payload class for cancer and SARS-CoV-2 infection therapies

Acta Pharmaceutica Sinica B. 2026, 16(2): 1046-1058.

Despite remarkable achievements in antibody-drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.

Carboxylated prodrug of capsaicin with enhanced peripheral nerve permeation mediated by monocarboxylate transporters for long-lasting local anesthesia

Acta Pharmaceutica Sinica B. 2026, 16(2): 994-1008.

Perineurally injected nerve-blocking agents have limited capability to cross peripheral nerve barriers (PNBs), requiring high doses to block pain signals on axons. This increases the risk of local tissue toxicity and systemic side effects on the cardiovascular and neurological systems. To address this, we explored carboxyl group modification to enhance the permeability of nerve-blocking agents across the PNBs through carrier-mediated transport facilitated by monocarboxylate transporters (MCTs). The enhanced permeability allows for targeted drug delivery to peripheral nerve axons, resulting in a significant reduction in the necessary drug dosage for a long-lasting nerve block. Specifically, we developed a carboxylated prodrug of capsaicin (COOH-CAP) by conjugating it with a carboxyl group via a degradable ester bond. Calcium flux assays, patch-clamp recordings, and body temperature measurements collectively confirmed that COOH-CAP activates TRPV1, with potency comparable to capsaicin. In rats, a single sciatic nerve injection of 3.28 μmol COOH-CAP produced a nociceptive-selective nerve blockade lasting 260 ± 83.7 h without motor impairment or capsaicin-related side effects, approximately 35 times longer than the same dose of plain capsaicin. Even at a lower dose of 1.64 μmol, COOH-CAP still produced nociceptive-selective nerve blockade for 172.0 ± 41.3 h.

A novel fusion protein of COVID-19 virus enhancing protection of Syrian hamsters infected with SARS-CoV-2

Acta Pharmaceutica Sinica B. 2026, 16(2): 900-912.

COVID-19 and its variants have spread around the world, triggering a range of long-term sequelae and leading to the need for broadly effective vaccines. We have established a new fusion protein combining the receptor-binding domain region (SF2) and a newly identified conserved binding region (SF5) from the spike of SARS-CoV-2. This fusion protein (COVID19-SF2+SF5) specifically bound to VERO-E6 cells with higher efficiency than either region alone. Antibodies raised in mice against COVID19-SF2+SF5 cross-reacted with every fragment of SARS-CoV-2 and SARS. Additionally, antibodies against the fusion protein effectively neutralize pseudoviruses of both wild-type and mutant strains of SARS-CoV-2 (including BA.3, XBB.1.5, and EG.5), as well as SARS pseudoviruses. Protein interaction prediction and binding affinity determination revealed that the fusion protein exhibits strong binding capacity to three key host molecules: heparan sulfate proteoglycan (HSPG), neuropilin-1 (NRP1), and cluster of differentiation 147 (CD147). Analysis of representative viruses from four coronavirus genera (α, β, γ, δ)—including 229E, NL63, OC43, HKU1, SARS-CoV, MERS-CoV, HKU20, and IBV—revealed that these coronaviruses share sequence similarity mainly on SF2 and SF5 regions. Furthermore, immunization of female hamsters with COVID19-SF2+SF5 provided significant protection against a SARS-CoV-2 virus challenge. Taken together, our results indicate that vaccination with a protein containing both an receptor binding domain (RBD) region and a common binding region provides strong protection during infection, thus suggesting a potential strategy to avoid evasion of host immune recognition by virus variants. Significantly, the observation that COVID19-SF2+SF5 immunization possesses stronger activity in reducing viral load at early stages suggests that the SF5 region might play an important role in virus recognition and binding to host cells. Based on these findings, we conclude that it is possible to develop universal vaccines and neutralizing monoclonal antibodies to curb the effects of mutations and to target multiple coronaviruses.

Complete biosynthesis of phenylspirodrimanes with unclustered genes in Stachybotrys chartarum

Jimei Liu, Ridao Chen, Min Zhang, Yangyang Duan, Keping Feng, Songyang Sui, Yaotian Han, Kebo Xie, Jun Wu, Haibo Yu, Dawei Chen, Jungui Dai

Acta Pharmaceutica Sinica B. 2026, 16(2): 966-978.

Phenylspirodrimanes are a class of structurally diverse meroterpenoids, including the bioactive dimer stachybocin A (1) and the high-reactivity monomer stachybotrydial (2), which are isolated from the genus Stachybotrys. Whereas the biosynthetic pathway of these phenylspirodrimane meroterpenoids has remained elusive. Herein, we deciphered the complete biosynthetic pathway of 2 with unprecedented two gene clusters and five discrete genes by genome mining, gene inactivation, heterologous expression, biochemical experiments, and especially combining with transcriptome-based hierarchical clustering and expression correlation analyses. Totally, 11 genes for the phenylspirodrimane core skeleton formation, 8′-methyl oxidation, and 3-OH epimerization were efficiently discovered and functionally characterized. Notably, these biosynthetic genes are distributed across seven distinct regions, with a rare combination of multiple gene clusters and genes outside the clusters. Bioactivity assays revealed that four intermediates 6-8, and 9a exhibited significant inhibitory effect on the inactivated state hNaV1.2 channels with IC₅₀ values of 0.15, 0.04, 0.28, and 1.91 μmol/L, respectively. These findings expand our understanding of phenylspirodrimane-type meroterpenoid biosynthesis and underscore the utility of transcriptome-based hierarchical clustering and expression correlation analyses for identifying unclustered biosynthetic genes in fungi.