Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy.

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy, but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration. Herein, we designed a cancer-associated fibroblasts (CAFs) triggered structure-transformable nano-assembly (HSD-P@V), which can directionally deliver valsartan (Val, CAFs regulator) and doxorubicin (DOX, senescence inducer) to the specific targets. In detail, DOX is conjugated with hyaluronic acid (HA) via diselenide bonds (Se-Se) to form HSD micelles, while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer, which is coated on Val nanocrystals (VNs) surface for improving the stability and achieving responsive release. Once arriving at tumor microenvironment and touching CAFs, HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment. VNs can degrade the extracellular matrix, leading to the enhanced penetration of HSD. HSD targets tumor cells, releases DOX to induce senescence, and recruits effector immune cells. Furthermore, senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy. In vitro and in vivo results show that the nano-assembly remarkably inhibits tumor growth as well as lung metastasis, and extends tumor-bearing mice survival. This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

hOGG1: A novel mediator in nitrosamine-induced esophageal tumorigenesis.

BACKGROUND: The effect of human 8-Oxoguanine DNA Glycosylase (hOGG1) on exogenous chemicals in esophageal squamous cell carcinoma (ESCC) remain unclear. The study plans to determine hOGG1 expression levels in ESCC and possible interactions with known environmental risk factors in ESCC. MATERIAL AND METHODS: We analyzed levels of exposure to urinary nitrosamines in volunteers from high and low prevalence areas by GC-MS. And we performed the interaction between hOGG1 gene and nitrosamine disinfection by-products by analyzing hOGG1 gene expression in esophageal tissues. RESULTS: In ESCC, nitrosamine levels were significantly increased and hOGG1 mRNA expression levels were significantly decreased. There was a statistically significant interaction between reduced hOGG1 mRNA levels and non-tap drinking water sources in ESCC. The apparent indirect association between ESCC and NMEA indicated that 33.4% of the association between ESCC and NMEA was mediated by hOGG1. CONCLUSION: In populations which exposed to high levels of environmental pollutants NDMA, low expression of hOGG1 may promote the high incidence of esophageal cancer in Huai'an. hOGG1 may be a novel mediator in nitrosamine-induced esophageal tumorigenesis.

Biomimetic Nanovehicle-Enabled Targeted Depletion of Intratumoral Fusobacterium nucleatum Synergizes with PD-L1 Blockade against Breast Cancer.

Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.

A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment.

Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood-brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2-fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging-mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti-inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1-fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.

Recent Advancements in Continuous-Flow Suzuki-Miyaura Coupling Utilizing Immobilized Molecular Palladium Complexes.

Immobilized Pd-catalyzed Suzuki-Miyaura coupling under continuous-flow conditions using a packed-bed reactor, representing an efficient, automated, practical, and safe technology compared to conventional batch-type reactions. The core objective of this study is the development of an active and durable catalyst. In contrast to supported Pd nanoparticles, the attachment of Pd complexes onto solid supports through well-defined coordination sites is considered a favorable approach for preparing highly dispersed and stabilized Pd species. These species can be directly employed in various flow reactions without the need for pre-treatment. This concept paper explores recent achievements involving the application of immobilized Pd complexes as precatalysts for continuous-flow Suzuki-Miyaura coupling. Our focus is to elucidate the significance of the designed catalyst structures in relation to their catalytic performance under flow conditions. Additionally, we highlight various reaction systems and catalyst packing methods, emphasizing their crucial roles in establishing a practical synthesis process.

Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.

Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4 °C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3 weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.

Capillary Manganese Halide Needle-Like Array Scintillator with Isolated Light Crosstalk for Micro-X-Ray Imaging.

The exacerbation of inherent light scattering with increasing scintillator thickness poses a major challenge for balancing the thickness-dependent spatial resolution and scintillation brightness in X-ray imaging scintillators. Herein, a thick pixelated needle-like array scintillator capable of micrometer resolution is fabricated via waveguide structure engineering. Specifically, this involves integrating a straightforward low-temperature melting process of manganese halide with an aluminum-clad capillary template. In this waveguide structure, the oriented scintillation photons propagate along the well-aligned scintillator and are confined within individual pixels by the aluminum reflective cladding, as substantiated from the comprehensive analysis including laser diffraction experiments. Consequently, thanks to isolated light-crosstalk channels and robust light output due to increased thickness, ultrahigh spatial resolutions of 60.8 and 51.7 lp mm-1 at a modulation transfer function (MTF) of 0.2 are achieved on 0.5 mm and even 1 mm thick scintillators, respectively, which both exceed the pore diameter of the capillary arrays' template (Φ = 10 µm). As far as it is known, these micrometer resolutions are among the highest reported metal halide scintillators and are never demonstrated on such thick scintillators. Here an avenue is presented to the demand for thick scintillators in high-resolution X-ray imaging across diverse scientific and practical fields.

Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

A Triple-Responsive Polymeric Prodrug Nanoplatform with Extracellular ROS Consumption and Intracellular H2 O2 Self-Generation for Imaging-Guided Tumor Chemo-Ferroptosis-Immunotherapy.

High reactive oxygen species (ROS) levels in tumor microenvironment (TME) impair both immunogenic cell death (ICD) efficacy and T cell activity. Furthermore, tumor escapes immunosurveillance via programmed death-1/programmed death ligand-1 (PD-L1) signal, and the insufficient intracellular hydrogen peroxide weakens ferroptosis efficacy. To tackle the above issues, a glutathione (GSH)/ROS/pH triple-responsive prodrug nanomedicine that encapsulates Fe2 O3 nanoparticle via electrostatic interaction is constructed for magnetic resonance imaging (MRI)-guided multi-mode theranostics with chemotherapy/ferroptosis/immunotherapy. The diselenide bond consumes ROS in TME to increase T cells and ICD efficacy, the cleavage of which facilitates PD-L1 antagonist D peptide release to block immune checkpoint. After intracellular internalization, Fe2 O3 nanoparticle is released in the acidic endosome for MRI simultaneously with lipid peroxides generation for tumor ferroptosis. Doxorubicin is cleaved from polymers in the condition of high intracellular GSH level accompanied by tumor ICD, which simultaneously potentiates ferroptosis by NADPH oxidase mediated H2 O2 self-generation. In vivo results indicate that the nanoplatform strengthens tumor ICD, induces cytotoxic T lymphocytes proliferation, inhibits 4T1 tumor regression and metastasis, and prolongs survival median. In all, a new strategy is proposed in strengthening ICD and T cells activity cascade with ferroptosis as well as immune checkpoint blockade for effective tumor immunotherapy.

A rare case report of Huntington's disease with severe psychiatric symptoms as initial manifestations.

INTRODUCTION: Huntington's disease (HD) stands as an inherited and progressive neurodegenerative ailment distinguished by chorea-esque movement patterns, which manifest as archetypal symptoms. The presence of pronounced psychiatric onset symptoms in patients can considerably amplify the intricacies of accurate diagnosis. CASE PRESENTATION: A 43-year-old gentleman was admitted with a five-year chronicle of delusions, hallucinations, and irritability. He had previously received a diagnosis of schizophrenia and had been subjected to a regimen of antipsychotic medications for a span exceeding four years. However, subsequent to the application of cerebral MRI and genetic testing, his condition was conclusively redetermined as HD. CONCLUSION: The salient attribute of this case resides in the deferred diagnosis of HD attributable to the presence of acute psychiatric initial symptoms, a scenario bearing noteworthy ramifications for disease oversight and prognostication. This instance warrants attentive scrutiny and discourse within the professional community.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8 pg mL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2 mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

Biochemotaxis-Oriented Engineering Bacteria Expressing GLP-1 Enhance Diabetes Therapy by Regulating the Balance of Immune.

Glucagon like peptide-1 (GLP-1) is an effective hypoglycemic drug that can repair the pancreas ß cells and promote insulin secretion. However, GLP-1 has poor stability and lacks of target ability, which makes it difficult to reach the site of action to exert its efficacy. Here, GLP-1-expressing plasmids are introduced into the Escherichia coli Nissle 1917 (EcN) and a lipid membrane is formed through simple self-assembly on its surface, resulting in an oral delivery system (LEG) capable of resisting the harsh environment of the gastrointestinal tract. The system utilizes the chemotactic properties of probiotics to achieve efficient enrichment at the pancreatic site, and protects islet ß cells from destruction by regulating the balance of immune cells. More interestingly, LEG not only continuously produces GLP-1 to restore pancreatic islet ß cell function and secrete insulin to control blood sugar levels, but also regulates the intestinal flora and increases the richness and diversity of probiotics. In mice diabetes models, oral administration of LEG only once every other day has good biosafety and compliance, and achieves long-term control of blood glucose. Therefore, this strategy not only provides an oral delivery platform for pancreatic targeting, but also opens up new avenues for reversing diabetes.

Liposomal Antibiotic Booster Potentiates Carbapenems for Combating NDMs-Producing Escherichia coli.

Infections caused by Enterobacterales producing New Delhi Metallo-ß-lactamases (NDMs), Zn(II)-dependent enzymes hydrolyzing carbapenems, are difficult to treat. Depriving Zn(II) to inactivate NDMs is an effective solution to reverse carbapenems resistance in NDMs-producing bacteria. However, specific Zn(II) deprivation and better bacterial outer membrane penetrability in vivo are challenges. Herein, authors present a pathogen-primed liposomal antibiotic booster (M-MFL@MB), facilitating drugs transportation into bacteria and removing Zn(II) from NDMs. M-MFL@MB introduces bismuth nanoclusters (BiNCs) as a storage tank of Bi(III) for achieving ROS-initiated Zn(II) removal. Inspired by bacteria-specific maltodextrin transport pathway, meropenem-loaded BiNCs are camouflaged by maltodextrin-cloaked membrane fusion liposome to cross the bacterial envelope barrier via selectively targeting bacteria and directly outer membrane fusion. This fusion disturbs bacterial membrane homeostasis, then triggers intracellular ROS amplification, which activates Bi(III)-mediated Zn(II) replacement and meropenem release, realizing more precise and efficient NDMs producer treatment. Benefiting from specific bacteria-targeting, adequate drugs intracellular accumulation and self-activation Zn(II) replacement, M-MFL@MB rescues all mice infected by NDM producer without systemic side effects. Additionally, M-MFL@MB decreases the bacterial outer membrane vesicles secretion, slowing down NDMs producer's transmission by over 35 times. Taken together, liposomal antibiotic booster as an efficient and safe tool provides new strategy for tackling NDMs producer-induced infections.

Cell Death Pathway Regulation by Functional Nanomedicines for Robust Antitumor Immunity.

Cancer immunotherapy has become a mainstream cancer treatment over traditional therapeutic modes. Cancer cells can undergo programmed cell death including ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis which are find to have intrinsic relationships with host antitumor immune response. However, direct use of cell death inducers or regulators may bring about severe side effects that can also be rapidly excreted and degraded with low therapeutic efficacy. Nanomaterials are able to carry them for long circulation time, high tumor accumulation and controlled release to achieve satisfactory therapeutic effect. Nowadays, a large number of studies have focused on nanomedicines-based strategies through modulating cell death modalities to potentiate antitumor immunity. Herein, immune cell types and their function are first summarized, and state-of-the-art research progresses in nanomedicines mediated cell death pathways (e.g., ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis) with immune response provocation are highlighted. Subsequently, the conclusion and outlook of potential research focus are discussed.

Interacting with luteinizing hormone receptor provides a new elucidation of the mechanism of anti-androgenicity of bisphenol S.

Bisphenol S (BPS) exhibited inhibitory effects on androgen synthesis, but its target of action remains unclear. We investigated the effects of BPS exposure at environmentally relevant concentrations (1 µg/L, 10 µg/L and 100 µg/L) for 48 h on androgen synthesis in rat ovarian theca cells and explored the underlying mechanisms, target site and target molecule. The results showed that BPS exposure inhibited the transcript levels of steroidogenic genes and reduced the contents of androgen precursors, testosterone and dihydrotestosterone. BPS exposure decreased the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2), and the inhibitory effects of BPS on testosterone content and steroidogenic gene expression were blocked by ERK1/2 agonist LY2828360, suggesting that ERK1/2 signaling pathway mediates the inhibitory effects of BPS on androgen synthesis. BPS mainly accumulated on the cell membrane, impermeable BPS-bovine serum albumin exposure still inhibited androgen synthesis, BPS interacted with rat luteinizing hormone receptor (LHR) via formation of hydrogen bonds in the transmembrane region, and the inhibitory effects of BPS on ERK1/2 phosphorylation were blocked by luteinizing hormone (the natural agonist of LHR), indicating that LHR located on the cell membrane is the target of action of BPS. This paper provides a new elucidation of the mechanism of anti-androgenicity of BPS, especially for the non-genomic pathways.

In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor.

Mutations in mitochondrial DNA (mtDNA) play critical roles in many human diseases. In vivo visualization of cells bearing mtDNA mutations is important for resolving the complexity of these diseases, which remains challenging. Here we develop an integrated nano Cas12a sensor (InCasor) and show its utility for efficient imaging of mtDNA mutations in live cells and tumor-bearing mouse models. We co-deliver Cas12a/crRNA, fluorophore-quencher reporters and Mg2+ into mitochondria. This process enables the activation of Cas12a's trans-cleavage by targeting mtDNA, which efficiently cleave reporters to generate fluorescent signals for robustly sensing and reporting single-nucleotide variations (SNVs) in cells. Since engineered crRNA significantly increase Cas12a's sensitivity to mismatches in mtDNA, we can identify tumor tissue and metastases by visualizing cells with mutant mtDNAs in vivo using InCasor. This CRISPR imaging nanoprobe holds potential for applications in mtDNA mutation-related basic research, diagnostics and gene therapies.

Light-driven micro/nanomotors in biomedical applications.

Nanotechnology brings hope for targeted drug delivery. However, most current drug delivery systems use passive delivery strategies with limited therapeutic efficiency. Over the past two decades, research on micro/nanomotors (MNMs) has flourished in the biomedical field. Compared with other driven methods, light-driven MNMs have the advantages of being reversible, simple to control, clean, and efficient. Under light irradiation, the MNMs can overcome several barriers in the body and show great potential in the treatment of various diseases, such as tumors, and gastrointestinal, cardiovascular and cerebrovascular diseases. Herein, the classification and mechanism of light-driven MNMs are introduced briefly. Subsequently, the applications of light-driven MNMs in overcoming physiological and pathological barriers in the past five years are highlighted. Finally, the future prospects and challenges of light-driven MNMs are discussed as well. This review will provide inspiration and direction for light-driven MNMs to overcome biological barriers in vivo and promote the clinical application of light-driven MNMs in the biomedical field.

Inhaled pulmonary surfactant biomimetic liposomes for reversing idiopathic pulmonary fibrosis through synergistic therapeutic strategy.

Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance. In this collaborative pulmonary drug delivery system, PSBs composed of DPPC/POPG/DPPG/CHO (20:9:5:4) were formulated for inhalation. These PSBs loaded with ROS-scavenger astaxanthin (AST) and anti-fibrosis drug pirfenidone (PFD) were aerosolized for precise quantification and mimicking patient inhalation. Through aerosol inhalation, the lipid membrane of PSBs gradually fused with natural PS, enabling AST delivery to AECs by hitchhiking with PS circulation. Simultaneously, PFD was released within the PS barrier, effectively penetrating lung tissue to exert therapeutic effects. In vivo results have shown that PSBs offer numerous therapeutic advantages in mice with IPF, particularly in terms of lung function recovery. This approach addresses the challenges of drug delivery to specific lung cells and offers potential benefits for IPF patients.