Clinical treatment effects of breast cancer are heavily frustrated by the malignant crosstalk between tumor vasculature and breast cancer stem cells (BCSCs). This study introduces a two-phase therapeutic strategy targeting the interplay between tumor vasculature and BCSCs to overcome this challenge. Here, we designed an FLG/ZnPc nanoscissor, which combines mild photodynamic therapy (PDT) to generate reactive oxygen species (ROS) with vascular normalization therapy (VNT) to break the crosstalk between tumor vessels and BCSCs. In the first phase, our approach breaks the vascular niche that supports BCSCs by restoring tumor vascular function and promoting ROS-induced BCSCs differentiation into less malignant forms, enhancing treatment sensitivity. The second phase employs high-impact photothermal therapy (PTT) to ablate tumor masses. This integrated "mild PDT-PTT" approach aims to reduce tumor growth and metastasis, offering a comprehensive strategy for effective breast cancer management.

Ferroptosis, a novel form of cell death, has emerged as a promising approach in cancer therapy. However, the single ferroptosis inducer was ineffective, and the induction of ferroptosis was severely limited by hypoxia niches in breast cancer. Herein, we develop a disulfide bond-bridging fluorinated doxorubicin (DOX) prodrug, which can facilitate the formation of hybrid nanoassemblies (NAs) with sorafenib (Sor) through a molecular co-assembly strategy. The incorporation of fluorinated side chains enhances the oxygen-carrying capacity of the NAs, successfully reversing the redox offensive and defensive situation caused by the dilemma of hypoxia. The reactive oxygen species (ROS) generation capacity of DOX via nicotinamide adenine dinucleotide oxidase (NOXs) within hypoxic tumors is significantly enhanced due to the presence of fluorinated oxygen-carrying as a catalytic substrate. Furthermore, the depletion of nicotinamide adenine dinucleotide phosphate (NADPH) significantly impairs the synthesis of glutathione (GSH), which collaboratively inhibits GSH production with Sor. As expected, the NAs with bidirectional amplification of ROS production and GSH inhibition displays potent antitumor activity in 4 T1 breast cancer-bearing mice. Together, this study presents a novel nanotherapeutic approach for ferroptosis-driven tumor therapy.

Parkinson's disease (PD)-induced motor dysfunction and cognitive impairment are becoming increasingly common due to global population aging. However, efficient treatment strategies for these conditions are still lacking. Recent studies indicated that neuroinflammation and neuronal apoptosis could greatly worsen the symptoms of PD. Therefore, anti-apoptotic and anti-inflammatory drugs could be useful in the management of PD. In the present study, minocycline (MIN)-loaded FeO nanoparticles (FeO-MIN NPs) were prepared for the targeted treatment of PD. Owing to their near-infrared (NIR) irradiation-induced photothermal effects, the FeO-MIN NPs could cross the blood-brain barrier (BBB), thus enhancing the delivery of FeO-MIN NPs to the brain parenchyma. Subsequently, the FeO-MIN NPs exerted strong anti-inflammatory effects and alleviated neuroinflammation in the brain. Furthermore, they exerted anti-oxidative effects, scavenging excessive reactive oxygen species in the brain parenchyma and thus protecting both dopaminergic and hippocampal neurons from neuroinflammation and apoptosis. Consequently, FeO-MIN NPs + NIR treatment attenuated the motor dysfunction and cognitive impairment observed in PD mice. Notably, the FeO-MIN NPs also showed high biocompatibility. Hence, these BBB-penetrating MIN-loaded FeO NPs demonstrate great therapeutic potential for PD accompanied by cognitive impairment.

Calcium (Ca) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca accumulation at the tumor site and suboptimal intracellular Ca influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca hydrogen phosphate nanowires (CHP) to achieve a synergistic approach for bone tumor therapy. GM@Lip@CHP-Gel selectively responded to the slightly acidic tumor microenvironment, triggering degradation of its 3D network structure and sustaining the release of GA and Ca into tumor cells. GA subsequently stimulated Ca influx in tumor cells, effectively disrupting Ca homeostasis. CHP nanowires served as a continuous Ca source, enhancing GA-mediated Ca overload and promoting mitochondrial apoptosis in tumor cells. The combined strategy resulted in an in vivo tumor suppression rate of 79 % and a lung metastasis inhibition rate of 89.4 %, with a protective effect on bone tissue. The naturally derived, Ca-mediated treatment demonstrated physiochemical stability in physiological environments and minimized side effects on healthy organs, positioning it as a promising approach for clinical bone cancer therapy.

Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injections in terms of compliance and convenience. However, significant challenges remain in terms of inactivation in gastrointestinal environment and limited permeation across the intestinal epithelium. Herein, we used acid-resistant metal-organic framework (PCN-222) to load insulin and modified the exterior with sodium dodecyl sulfate (SDS) to achieve efficient oral insulin delivery. The PCN-222 nanocarrier with ordered mesoporous cage structure and suitable pore size achieved a high insulin loading of 75 %. The SDS on the surface of nanocarrier reduces its hydrophilicity while reversibly altering cell morphology and increasing epithelial cell permeability, thereby promoting intestinal epithelial absorption. The constructed particle (I@P@S) was encapsulated in sodium alginate (SA) microspheres to protect it from gastric acid degradation and releases it upon entry into the intestinal tract. Through an uptake pathway dominated by clathrin-mediated endocytosis, the released I@P@S realized efficient intestinal permeability and controlled insulin release under physiological conditions due to the phosphate sensitivity of PCN-222, leading to an in vivo bioavailability of 12.9 %. This work provides a valuable reference for the design of oral insulin delivery systems.

Persistent reactive oxygen species (ROS) and neuroinflammation contribute to the onset and progression of neurodegenerative diseases, underscoring the need for targeted therapeutic strategies to mitigate these effects. Extracellular vesicles (EVs) show promise in drug delivery due to their biocompatibility, ability to cross biological barriers, and and specific interactions with cell and tissue receptors. In this study, we demonstrated that human plasma-derived EVs (pEVs) exhibit higher brain-targeting specificity, while adipose-derived mesenchymal stem cells EVs (ADMSC-EVs) offer regenerative and immunomodulatory properties. We further investigated the potential of these EVs as therapeutic carriers for brain-targeted drug delivery, using Donepezil (DNZ) as the model drug. DNZ, a cholinesterase inhibitor commonly used for Alzheimer's disease (AD), also has neuroprotective and anti-inflammatory properties. The size of EVs used ranged from 50 to 300 nm with a surface charge below -30 mV. Both formulations showed rapid cellular internalization, without toxicity, and the ability to cross the blood-brain barrier (BBB) in a zebrafish model. The have analyzed the anti-inflammatory and antioxidant actions of pEVs-DNZ and ADMSC-EVs-DNZ in the presence of lipopolysaccharide (LPS). ADMSC-EVs significantly reduced the inflammatory mediators released by HMC3 microglial cells while treatment with pEVs-DNZ and ADMSC-EVs-DNZ lowered both phagocytic activity and ROS levels in these cells. In vivo experiments using zebrafish larvae revealed that both EV formulations reduced microglial proliferation and exhibited antioxidant effects. Overall, this study highlights the potential of EVs loaded with DNZ as a novel approach for treating neuroinflammation underlying various neurodegenerative diseases.

The high mortality rate associated with metastatic breast cancer presents a significant global challenge. Inherent and chemotherapy-induced DNA damage repair, alongside immunosuppression, drastically contribute to triple-negative breast cancer (TNBC) relapse and metastasis. While poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib show effectiveness against BRCA1-mutant TNBC, they may lead to drug resistance and reduced efficacy due to increased programmed death-ligand 1 (PD-L1) expression. Our study explored the use of polymer-lipid nanoparticles (PLN) loaded with doxorubicin (DOX) and oligomeric hyaluronic acid (oHA), functionalized iRGD-peptide for integrins targeting (iRGD-DOX-oHA-PLN), to prevent TNBC immunosuppression, DNA repair, and metastasis. The results demonstrate that the iRGD-DOX-oHA-PLNs efficiently downregulated single and double-strand DNA repair proteins and enhanced DNA damage while decreasing PD-L1 expression compared to olaparib. Accordingly, iRGD-DOX-oHA-PLN treatment showed significantly higher efficiency in reducing levels of primary tumor growth and numbers of metastases to the lung and liver compared to olaparib in vitro and in vivo in both BRCA1-mutant and wild type TNBC orthotopic xenograft models.

Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis. Specifically, we describe the lab-scale formulation development, preclinical mucosal safety and pharmacokinetics (PK) testing in rabbits, long-term stability, and scale-up clinical manufacturing of the lead TAF/EVG (20 mg/16 mg) inserts, which are currently in clinical stages of development. As designed, the inserts are small, discreet and portable, offering a number of promising attributes, such as simple and robust direct-compression manufacturing, fast initial disintegration/dissolution, and suitable mechanical strengths showing low hardness (<8 kg), friability (<1 %), and moisture content (<1 %). The inserts initiated disintegration quickly (~ ≤ 15 min) providing full in vitro release (>90 %) of TAF and EVG within 60 min of dissolution. The lead insert was selected from formulation prototypes that met the evaluation criteria for manufacturability and characterization, together with a dose-ranging PK study in non-human primates. Successful technology transfer for clinical development of the lead TAF/EVG (20 mg/16 mg) insert was confirmed under cGMP conditions. Based on the 12 months (lab-scale) and 24 months (clinical batch) stability data, the TAF/EVG inserts are projected to have a long shelf life of over 2 years, if stored at or below 30 °C/65 % RH. Overall, these newly designed topical inserts have formulation properties that enable stable storage and fast release of the antiretroviral payload from a small, portable and discreet dosage form. They are safe and effective when applied vaginally or rectally, before or after coitus, providing the basis for a new method of flexible on-demand HIV prevention for cisgender and transgender women and men. The TAF/EVG inserts are currently the most clinically advanced on-demand topical product, as attested by their completed and ongoing clinical trials.

The demand for new antibacterial therapies is urgent and crucial in the clinical setting because of the growing degree of antibiotic resistance and the limits of conventional antibacterial therapies. Stimuli- responsive nanoplatforms, are sensitive to endogenous or exogenous stimulus (pH, temperature, light, and magnetic fields, etc.) which activate cargo release locally and on-demand, hold great potential in developing next generation personalized precision medicine. For instance, pH-sensitive nanoplatforms can selectively release antibacterial agents in the acidic environment of infection sites. To achieve the stimuli-responsive delivery, mesoporous silica nanoplatforms (MSNs) have demonstrated as prospective candidates for efficient cargo loading and controlled release through strategies such as tunable pore engineering, versatile surface modification/coating, and tailored framework composition. Furthermore, aiming for more precise delivery of MSNs, current research interests are increasingly shifting from single-stimuli antibacterial strategy to integrated strategy that combine multiple-stimulus. In this review, we briefly discuss the microenvironment of bacterial infections and provide a comprehensive summary of current stimuli-responsive strategies, and associated materials design principles of stimuli-responsive mesoporous silica-based smart nanoplatforms (SRMSNs). Additionally, integrative antibacterial strategies with synergistic effects, combining chemodynamic, photodynamic, photothermal, sonodynamic and gas therapies, have also been elaborated. Present research advances and limitations of SRMSNs-based antibacterial therapies, such as limited biodegradability and potential cytotoxicity, have been overviewed with future outlooks presented. This review aims to inspire and guide future research in developing novel antibacterial strategies with integrative solutions.

Occlusive blood clots remain a significant global health challenge and result in emergencies that are main causes of death and disability worldwide. Thrombolytic agents (including tissue plasminogen activator, tPA) are the only pharmacological means to dissolve blood clots. However, these drugs have modest efficacy and severe safety concerns persist. We have developed light-responsive tPA-loaded red blood cells (tPA-RBCs) to target thrombolytic activity at the site of a blood clot. Herein, we describe the use of light to control the release of tPA from engineered RBCs and the subsequent degradation of a blood clot ex vivo. Furthermore, we have employed this technology to restore blood flow to an occluded mouse artery in vivo using a targeted dose that is 25 times lower than conventional systemic tPA treatment.

Crohn's Disease and Ulcerative Colitis, the main types of Inflammatory Bowel Disease (IBD), are life-threatening gastrointestinal disorders with no definitive cure. The establishment of biorelevant in vitro models that closely recapitulate the IBD microenvironment is of utmost importance to validate newly developed IBD therapies. To address the existing flaws in the current representation of the IBD microenvironment, we propose a novel three-dimensional (3D) in vitro model comprising a multi-layered gastrointestinal tissue with functional immune responses under inflammatory conditions. The multi-layered architecture consists of a lamina propria-like hydrogel with human intestinal fibroblasts (HIF), supporting an epithelial layer composed of Caco-2 and HT29-MTX cells, along with an endothelial layer surrogating the absorptive capillary network. A collagen-alginate composite matrix was optimized for the lamina propria-like hydrogel, preserving HIF metabolic activity and morphology over time. To achieve immune competence, pre-differentiated THP-1-derived macrophages were incorporated into the epithelial barrier. Inflammation was induced through the optimization of an inflammatory cocktail consisting of E. coli O111:B4 lipopolysaccharide combined with a specialized cytokine array (tumor necrosis factor-α, interferon-γ, and interleukin-1β). This inflammation-inducing stimulus led to a significant upregulation of pro-inflammatory cytokines commonly associated with IBD onset, including CCL20, IL-6, CXCL9 and CXCL10. Altogether, this 3D in vitro model has the potential to accelerate the drug development pipeline by providing reliable permeability and efficacy outputs for emerging therapies, reducing unnecessary animal experiments. Moreover, it offers a valuable in vitro platform for studying IBD pathophysiology and cell interplay dynamics.

Musculoskeletal conditions impact 1.71 billion individuals, posing significant challenges due to their complexity, varying clinical courses, and unclear molecular mechanisms. Conventional spectrum treatments often prove inadequate, underscoring the importance of targeted therapies. Recently, RNA-based technologies have emerged as a groundbreaking approach in therapeutics, showing applications in joint related ailments. This perspective aims to examine endeavors exploring the use of RNA-based treatments in both experimental and clinical contexts for addressing joint issues like osteoarthritis, rheumatoid arthritis, and cartilage injuries. The cited studies demonstrate how mRNA can stimulate the production of proteins that aid in controlling inflammation, fostering tissue regeneration and repairing cartilage damage. In summary, this perspective offers an overview of the progress made in mRNA-based technologies for treating related conditions by highlighting favorable findings from preclinical research and encouraging results from clinical trials. With advancements in the field, mRNA therapeutics have the potential to revolutionize treatment approaches for musculoskeletal disorders, bringing renewed hope to the future of musculoskeletal conditions.

Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease that leads to severe joint damage and disability. Conventional treatment options are limited by their efficacy and side effect profiles. Nanozymes, nanomaterials with enzyme-like activities, offer a novel therapeutic approach for RA. This review summarizes recent advances in nanozyme-based treatments, focusing on their antioxidant and immunomodulatory roles in mitigating RA. We discuss various nanozymes, including those based on cerium, iron, manganese, silver, copper, platinum, rhodium, and multi-metallic nanozymes, which mimic natural enzymes such as superoxide dismutase, catalase, and peroxidase to reduce oxidative stress. Additionally, we explore nanozyme-based combination therapies that integrate with other strategies, such as vesicles and phototherapy, to achieve synergistic effects and enhance efficacy. This review highlights the significant potential of nanozymes in improving RA treatment, offering a new perspective for future research and clinical applications.

The COVID-19 pandemic has accelerated pre-clinical and clinical development of microneedle-based drug delivery technology. However the regulatory science of this emerging dosage form is immature and explicit regulatory guidance is limited. A group of international stakeholders has formed to identify and address key issues for the regulatory science of future products that combine a microneedle device and active pharmaceutical ingredient (in solid or semi-solid state) in a single entity that is designed for application to the skin. Guided by the principles of Quality by Design (QbD) and informed by consultation with wider stakeholders, this 'White Paper' describes fundamental elements of the work in an effort to harmonise understanding, stimulate discussion and guide innovation. The paper discusses classification of the dosage form (combination / medicinal product), the regulatory nomenclature that is likely to be adopted and the technical vocabulary that best describes its form and function. More than twenty potential critical quality attributes (CQAs) are identified for the dosage form, and a prioritisation exercise identifies those CQAs that are most pertinent to the dosage form and that will likely require bespoke test methods (delivered dose, puncture performance) or major adaptions to established compendial test methods (dissolution). Hopefully the work will provide a platform for the development of dosage form specific guidance (from regulatory authorities and/or international pharmacopoeias), that expedites clinical translation of safe and effective microneedle-based products.

New crosslinked polyesters, which are fully degradable in the presence of water over several months in the environment, were synthesized by direct polyesterification of multi-hydroxylic alcohols (e.g., pentaerythritol or glycerol), multi-carboxylic acids (e.g., citric acid), and hydroxy acid compounds (e.g., lactic acid). The reaction produced a crosslinked matrix with mechanical properties of solid and useful degradability in the environment. This reaction can be performed with moderate heat (100-200 °C) and without requiring the aid of additional catalysts, inert gas, or vacuum. The crosslinked matrix can be thermoplastic or thermoset, depending on the extent of crosslinking, which is controlled by reaction time and temperature. The polyesters formed with various ratios of the monomers degrade in water in 12 h at 95 °C, 3 days at 70 °C, and about 3 months at 30 °C. These environmentally degradable alkyl polyesters include a range of mechanical strengths and elasticity, making them suitable for various applications. These environmentally degradable, synthetic polymers can replace current non-degradable polymers in various applications. These new polymers are named "Nuplons".

Small interfering RNA (siRNA) that inhibit the formation of α-synuclein (α-syn) aggregates is considered very promising therapeutic agents for the treatment of Parkinson's disease (PD). However, the low stability and the difficulty in crossing the blood-brain barrier (BBB) of free siRNA has severely limited their therapeutic effects. Here, we developed an HS donor nanomotor that can encapsulate siRNA, which can both protect the activity of siRNA and help siRNA to be effectively targeted to the mitochondria of damaged neuronal cells, in order to promote the effective therapeutic effect of siRNA for PD. Specifically, the cysteine monomer-modified polyethylene glycol (PEG-Cys) and the amphiphilic ionic monomer 2-methacryloyloxyethylphosphorylcholine (MPC) that can effectively penetrate the BBB, were selected to form a polymer protective layer on the surface of siRNA in a free-radical polymerization reaction, to construct the HS donor nanomotor encapsulating siRNA (PCM@siRNA). Among them, MPC can help PCM@siRNA to break through the BBB by interacting with nicotinic acetylcholine receptor or choline transporter on the surface of cerebrovascular endothelial cells, while PEG-Cys can undergo chemotactic effect by specifically recognizing 3-thiopyruvate thioltransferase and thus achieve effective targeting of damaged mitochondria in neuronal cells. PCM@siRNA that reached neuronal cells can not only be utilized to play the role of silencing the α-syn gene to inhibit the formation of α-syn aggregates by siRNA, but also to degrade the formed α-syn aggregates by using the HS produced by its chemotaxis process to achieve an effective treatment for PD. This therapeutic modality, which can simultaneously inhibit the formation of α-syn aggregates and promote their degradation, has the therapeutic potential to reverse the pathological state of α-syn, which is important for the treatment of PD.

Camptothecin (CPT) and podophyllotoxin (PPT) function as topoisomerase (TOP) I and tubulin inhibitors, respectively, with potent anticancer effects in a variety of cancers. Despite its promise, the clinical applicability of the combination of CPT and PPT faces challenges, including potential side effect and limited therapeutic efficacy. In this study, we designed co-assembly nanomedicines with the different weight (w/w) ratios of amphiphilic Evans blue conjugated CPT prodrug (EB-ss-CPT) and PPT molecules, denoted as ECT Nano. The co-assembly of EB-ss-CPT and PPT without other excipients has nearly 100% drug loading efficiency and high drug loading content of PPT of up to 74.29 ± 0.90 wt%. Notably, the ECT Nano (1:2) equipped with the ability to inhibit TOP I activity and tubulin polymerization, which provided a highly efficient strategy to improve synergistic efficacy and decrease side toxicity in non-small cell lung cancer mouse model. This work represents a step forward to the development of practical applications for dual TOP I and tubulin inhibitors and especially hopeful to the rational design of combination nanomedicine for therapeutic purposes.

Intestinal mucosal barrier loss is responsible for the chronic and recurrent ulcerative colitis. Myosin light chain kinase (MLCK) is a potential therapeutic target of the intestinal mucosal barrier dysfunction. Here, we developed a reactive oxygen species (ROS)-sensitive hydrogel (ATG-CS-Gel) derived from a diselenide-bridged arctigenin (ATG) and chitosan (CS) conjugate, with the aims of targeting to inflamed mucosa and modulating MLCK. Our results demonstrated that ATG-CS-Gel achieved ROS-responsive release and significantly inhibited ROS production and mitochondrial depolarization in the Caco-2 and HT-29/MTX-E12 cells under HO-induced stress conditions. Compared with normal tissues, orally-administrated ATG-CS-Gel preferentially adhered to the inflamed mucosa for 24 h, which was attributed to the adhesion between CS and mucin. Therapeutically, ATG-CS-Gel reduced inflammatory symptoms, accelerated intestinal mucosal healing, scavenged excessive ROS, reshaped intestinal flora, and eventually achieved much better therapeutic efficacy in DSS-induced colitis mice when compared to 5-aminosalicylic acid. Moreover, ATG-CS-Gel was demonstrated to reverse intestinal mucosal barrier loss by blocking MLCK activation and maintaining tight junction expression. In summary, this study highlights the potential of MLCK modulation in the restoration of intestinal mucosal barrier using ATG-CS-Gel. The development of ATG-CS-Gel represents a novel and promising strategy for the treatment of ulcerative colitis.

Efficient and noninvasive drug delivery for glaucoma therapy necessitates prolonged retention on the ocular surface and deep penetration into the cornea. However, inherent physiological defenses such as rapid tear clearance and low cornea permeability present significant challenges that hinder the effectiveness of trans-corneal drug delivery. In this study, we demonstrate the potential of zwitterionic micelles composed of poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)-block-poly(ε-caprolactone) (OPDEA-PCL) amphiphiles as a biocompatible carrier for trans-corneal drug delivery. These micelles exhibit enhanced adhesion to ocular tissues and resistance to tear clearance due to their unique affinity for cell membranes. These characteristics facilitate adsorptive-mediated transcytosis, significantly augmenting trans-corneal transport and intraocular accumulation of the glaucoma medication brinzolamide (BRZ). As a result, OPDEA-PCL/BRZ formulations effectively normalize intraocular pressure in an open-angle glaucoma rat model, surpassing PEGylated and free BRZ formulations. This research underscores the potential utility of OPDEA-PCL micelles as a promising vehicle for noninvasive topical trans-corneal drug delivery in glaucoma therapy.

Treatment of solid tumors remains difficult, and therefore there has been increased focus on chimeric antigen receptor macrophages (CAR-M) to challenge solid tumors. However, CAR domain design of of adoptive cell therapy, which leads to differences in antitumor activity and triggered antitumor potential, remains poorly understood for macrophages. We developed an α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component for CAR-M specific activation and its antitumor potential. We evaluated CAR-M effects with α1β1 integrin-mediated FcγRI signaling (ACT CAR-M) on the activation and antitumor phagocytic response of macrophages in vitro. Subcutaneous tumor model in BALB/c mice and carcinomatosis model in immunodeficient mice were used to test the antitumor effect of ACT CAR-M compared with CD3ζ CAR-M. The α1β1 integrin-mediated FcγRI signaling engagement of CAR-M was associated with enhanced macrophage activation and specific phagocytosis in primary human macrophages, and significantly improved tumor control and survival in multiple cancer models when compared to CD3ζ CAR-M. RNA-sequencing suggested that α1β1 integrin-mediated FcγRI engagement increased antitumor immunity by enhancing pro-inflammatory M1 phenotype-associated pathways, such as Toll-like receptor signaling, tumor necrosis factor signaling, and IL-17 signaling. α1β1 integrin-mediated FcγRI signaling engagement markedly enhanced antitumor effects of CAR-M immunotherapy, which is proposed as an advanced engineering CAR domain material to expand the clinical application of CAR-M.