Hong Wu

Chemodynamic therapy (CDT) is severely limited by inadequate intracellular H ₂ O ₂ and frequent apoptosis resistance. Herein, a porous Fe ₃ O ₄ nanoplatform is engineered through coating of Fe ^{3 +} ‐tannic acid complex onto nanoclusters simultaneously loaded with carbonyl cyanide 3‐chlorophenylhydrazone (CCCP, a mitochondrial uncoupler) and lactate oxidase (LOD). By self‐supplying H ₂ O ₂ and concurrently blocking autophagic flux, this system is engineered to potentiate CDT efficacy. Beyond the expected therapeutic outcome, we uncover that this nanoplatform triggers an unconventional cell death pathway—paraptosis. Acid‐triggered dissociation in the tumor microenvironment releases Fe ^{2 +} /Fe ^{3 +} for Fenton reactions while LOD simultaneously converts lactate to H ₂ O ₂ , overcoming the H ₂ O ₂ bottleneck. CCCP further synergizes this process by collapsing the mitochondrial membrane potential, which amplifies ROS leakage and culminates in an oxidative storm. This dramatic surge in ROS directly induces mitochondrial dysfunction and initiates endoplasmic reticulum stress, while also suppressing autophagic flux. Collectively, these multi‐organelle stresses markedly exacerbate intracellular damage and lead to paraptotic cell death, characterized by extensive cytoplasmic vacuolization, eliciting robust immunogenic cell death. Combined with αPD‐L1, the nanoplatform potently activates antitumor immunity and suppresses both primary and distant tumors. This work pioneers a paraptosis activation strategy driven by an iron‐based nanodrug, redefining CDT efficacy through multi‐organelle stress synergy for amplified immunotherapy.

Efficient and uniform delivery of nanomedicine into deep tumors remains challenging due to the limited targeting efficiency and the dense stromal barrier o

We report a nanoparticle system based on PMLA to enhance drug delivery, improve cellular uptake, and achieve controlled intracellular drug release owing to enzyme-sensitive linker named AANL and pH-sensitive bond named cis-aconitic anhydride bond.

Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.

Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.

Purpose: The remarkable peroxidase-like activity of single-atom nanozymes (SAzymes) allows them to catalyze the conversion of H₂O₂ to •OH, rendering them highly promising for antibacterial applications. However, their practical in vivo application is hindered by the near-neutral pH and insufficient H₂O₂ levels present in physiological systems. This study was aimed at developing a SAzyme-based nanoreactor and investigating its in vivo antibacterial activity. Methods: We developed a hollow mesoporous molybdenum single-atom nanozyme (HMMo-SAzyme) using a controlled chemical etching approach and pyrolysis strategy. The HMMo-SAzyme not only exhibited excellent catalytic activity but also served as an effective nanocarrier. By loading glucose oxidase (GOx) with HMMo-SAzyme and encapsulating it with hyaluronic acid (HA), a nanoreactor (HMMo/GOx@HA) was constructed as glucose-triggered cascade catalyst for combating bacterial infection in vivo. Results: Hyaluronidase (HAase) at the site of infection degraded HA, allowing GOx to convert glucose into gluconic acid and H₂O₂. An acid environment significantly enhanced the catalytic activity of HMMo-SAzyme to promote the further catalytic conversion of H₂O₂ to •OH for bacterial elimination. In vitro and in vivo experiments demonstrated that the nanoreactor had excellent antibacterial activity and negligible biological toxicity. Conclusion: This study represents a significant advancement in developing a cascade catalytic system with high efficiency based on hollow mesoporous SAzyme, promising the advancement of biological applications of SAzyme.