Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene–laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient–derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell–specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.

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Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein‐based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re‐epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein‐condensed mRNA core, a bifunctional peptide‐modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in the alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif‐grafted cores then expose and specifically target the integrin‐elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re‐epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin‐induced murine model. Therefore, this work provides an alternative mRNA‐inhalation delivery strategy, which shows great potential for the treatment of IPF.

Locoregional delivery of chimeric antigen receptor (CAR)-modified T (CAR-T) cells has emerged as a promising strategy for brain tumors. However, the complicated ex vivo cell manufacturing procedures and the rapid progression of the disease have limited its broader applications. Macrophages (MΦs) exhibit unique effector functions and a high degree of infiltration within the solid tumor microenvironment (TME), especially in the brain, where MΦs function as structural support, and the main immune effector cells of the CNS represent 5–12% of brain cells. Here, we report a synthetic universal DNA nanocarrier for in situ genetic editing of intratumoral MΦs with an ErbB2-specific CAR to direct their phagocytic activity towards tumors and subsequently initiate a locoregional antitumor immune response. Specifically, we demonstrated that when delivered locoregionally, the RP-182 peptide, located in the shell of a nanoparticle, targeted MΦs and reprogrammed M2-like tumor-associated macrophages (TAMs) to an antitumor M1-like phenotype. Subsequently, the CAR gene-laden DNA nanocomplex can be used to introduce ErbB2-targeted CAR, and the generated CAR-MΦs then act as “living” cures, thereby serially clearing the invasive tumor cells. Our work demonstrates a practical antitumor immunotherapy for brainstem gliomas (BSGs) that may be broadly applicable for patients suffering from other ErbB2-positive solid malignancies.

Rationale: Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment. Methods: With the aid of polyphenol gallic acid, Cu 2+ ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative. In hypoxic tumor, the liposomal shell disintegrated, and a shrunk-size bio-nanoreactor was burst released. Intracellularly, Cu 2+ from the bio-nanoreactor catalyzed a Fenton-like reaction with glutathione, which efficiently converted H 2 O 2 to •OH and enabled a chemodynamic therapy (CDT) in tumor sites. With the alleviation of proangiogenic factor-mediated immunotolerance and high production of CDT-induced tumor-associated antigens, robust tumoricidal immunity was co-stimulated. Results: With colorectal tumor and its liver metastasis models, we determined the underlying mechanism of proangiogenic factor-mediated immunotolerance and highlighted that the liposomal bio-nanoreactor could create positive feedback among the critical players in the vascular endothelium and synergize the elicited tumoricidal immunity. Conclusion: Our work provides an alternative strategy for exerting efficient tumoricidal immunity in the proangiogenic factor-upregulated subpopulation of CRC patients and may have a wide-ranging impact on cancer immune-anti-angiogenic complementary therapy in clinics.