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As a major component of tumor infiltration, tumor‐associated macrophages (TAMs) primarily promote the M2 phenotype of tumors in the tumor microenvironment. Additionally, the overexpression of anti‐phagocytic molecules in TAMs facilitates tumor cell evasion of TAMs’ phagocytic arrest. Therefore, there is an urgent need to develop a reliable strategy to reprogram TAMs for more effective anti‐tumor outcomes. In this study, innovative inhalable bioorthogonal gene‐editable microparticles (SPR) have been engineered that reprogram TAMs for lung cancer therapy based on spike‐covered sunflower sporopollenin exine capsules (SECs). These microparticles utilize SECs as delivery vehicles, with reduced palladium (Pd) nanoparticles on their surface carrying CRISPR/Cas9 lipid nanoparticles (LNP‐RNPs) that specifically knock down the anti‐phagocytic SIRPα gene on TAMs. The SPR microparticles employ a tripartite strategy to reprogram the TAMs: the physical stimulation through pollen spikes, the production of a Toll‐like receptor 7 agonist (imiquimod, IMD) via Pd‐mediated bioorthogonal catalysis, and the employment of CRISPR/Cas9 gene editing. In an orthotopic mouse model, the inhalation of SPR microparticles not only reprograms macrophages efficiently but also bolsters their tumor‐fighting abilities. Notably, the cured mice show no signs of recurrence even upon re‐exposure to the tumor, indicating a long‐lasting anti‐tumor effect. [ABSTRACT FROM AUTHOR]

Renal clearance is critical for nanodrug to avoid the long‐term body retention‐related side effects, while it is difficult to achieve efficient tumor accumulation and retention. The over‐developed lysosomes in cancer cells have become an emerging target for more precise and effective cancer therapy. Herein, a pH‐responsive reversible self‐assembled Cu2‐xSe‐BSA, which can be renal cleared under neutral or basic conditions, is developed for selectively targeted aggregation in cancer lysosomes with enhanced tumor accumulation and retention. Moreover, the aggregation of Cu2‐xSe‐BSA can enhance the photoacoustic imaging signal, photothermal therapy, and chemodynamic therapy capability. Cu2‐xSe‐BSA accumulated in lysosomes cannot only induce lysosomes swelling, but also generate reactive oxygen species in situ, causing lysosomal membrane permeabilization and finally lysosomal cell death. Notably, the assembled Cu2‐xSe‐BSA can dissociate to be renal clearable after the treatments are completed and left the acid tumor microenvironment, being of great significance both in scientific research and clinical trial. [ABSTRACT FROM AUTHOR]