Although certain therapeutic agents with immunogenic properties may enhance antitumor immunity, cancer cells can eliminate harmful cytoplasmic entities and escape immunosurveillance by orchestrating autophagy. Here, an ingenious in situ self-assembled nanomicelle dissolving microneedle (DMN) patch was designed for intralesional delivery of immunogenic cell death-inducer (IR780) and autophagy inhibitor (chloroquine, CQ) coencapsulated micelles (C/I-Mil) for efficient antitumor therapy. Upon insertion into skin, the self-assembled C/I-Mil was generated, followed by electrostatic binding of hyaluronic acid, the matrix material of DMNs, accompanied by the dissolution of DMNs. Subsequently, photothermal-mediated size-tunable C/I-Mil could effectively penetrate into deep tumor tissue and be massively internalized via CD44 receptor-mediated endocytosis, precisely ablate tumors with the help of autophagy inhibition, and promote the release of damage-associated molecular patterns. Moreover, CQ could also act as an immune modulator to remodel tumor-associated macrophages toward the M1 phenotype via activating NF-κB. In vivo results showed that the localized photoimmunotherapy in synergy with autophagy inhibition could effectively eliminate primary and distant tumors, followed by a relapse-free survival of more than 40 days via remodeling the tumor immunosuppressive microenvironment. Our work provides a versatile, generalizable framework for employing self-assembled DMN-mediated autophagy inhibition integrated with photoimmunotherapy to sensitize superficial tumors and initiate optimal antitumor immunity.

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Combination therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR TKIs) with other chemotherapeutic agents is a feasible strategy to overcome resistance that often occurs after 9–13 months of EGFR TKIs administration in nonsmall cell lung cancer (NSCLC). In this study, a pulmonary microspheres system that codelivers afatinib and paclitaxel (PTX) is developed for treatment of EGFR TKIs resistant NSCLC. In this system, afatinib is loaded in stearic acid‐based solid lipid nanoparticles, then these nanoparticles and PTX are loaded in poly‐lactide‐co‐glycolide‐based porous microspheres. These inhaled microspheres systems are characterized including geometric particle size, drug encapsulation efficiency, morphology by scanning electron microscopy, specific surface area, in vitro drug release, and aerodynamic particle size. Cell experiments indicate that afatinib and PTX have a synergistic effect and the codelivery system shows a superior treatment effect in drug‐resistant NSCLC cells. The biocompatibility, pharmacokinetic, and tissue distribution experiments in Sprague–Dawley rats show that afatinib and PTX in the system can maintain 96 h of high lung concentration but low concentration in other tissues, with acceptable safety. These results demonstrate that this system may be a prospective delivery strategy for drug combination treatment in cancers developing resistance, especially drug‐resistant lung cancer.

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Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC­(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system Xc –) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.

Black phosphorus (BP) nanosheets emerged as promising 2D nanomaterial that have been applied to eradicate antibiotic-resistant bacteria. However, their applications are limited by intrinsic ambient instability. Here, the 𝝐-poly-l-lysine (𝝐-PL)-engineered BP nanosheets are constructed via simple electrostatic interaction to cater the demand for passivating BP with amplified antibacterial activity. The dual drug-delivery complex named BP@𝝐-PL can closely anchor onto the surface of bacteria, leading to membrane disintegration. Subsequently, in situ hyperthermia generated by BP under near-infrared (NIR) irradiation can precisely eradicate pathogenic bacteria. In vitro antibacterial studies verify the rapid disinfection ability of BP@𝝐-PL against Methicillin-resistant Staphylococcus aureus (MRSA) within 15 min. Moreover, 𝝐-PL can serve as an effective protector to avoid chemical degradation of bare BP. The in vivo antibacterial study shows that a 99.4% antibacterial rate in a MRSA skin infection model is achieved, which is accompanied by negligible toxicity. In conclusion, this work not merely provides a new conjecture for protecting the BP, but also opens a novel window for synergistic antibiotic-resistant bacteria therapy based on antimicrobial peptides and 2D photothermal nanomaterial.

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