AND-gated dual-responsive nanogels for spatiotemporally controlled codelivery of a PPARδ antagonist and anti-PD-1 antibody

Immune checkpoint blockade (ICB) remains limited by the immunosuppressive tumor microenvironment (TME) and by the difficulty of coordinating therapeutic agents that act in distinct tumor compartments. In particular, checkpoint antibodies must function in the tumor stroma, whereas TME-remodeling small molecules often require intracellular access, creating an extracellular–intracellular delivery mismatch that conventional carriers rarely resolve. Here, we develop an acid-gated, esterase-amplified AND-gated dendritic nanogel (DNG) for the spatiotemporally sequential codelivery of anti-PD-1 antibody (aPD-1) and the PPARδ antagonist GSK3787. The DNG comprises a PEG corona for reversible aPD-1 adsorption and a hydrophobic dendritic core for GSK3787 encapsulation. Under the combined cues of tumor acidity and esterase activity, the nanogel undergoes progressive dissociation, triggering preferential extracellular release of aPD-1 in the tumor stroma, followed by tumor-cell internalization of the GSK3787-loaded core for intracellular drug action. This AND-gated design enables spatially resolved pharmacology rather than simple codelivery. In a melanoma model, DNG@(GSK3787 + aPD-1) markedly enhances antitumor efficacy, thereby promotes CD8⁺ T cell infiltration, and elicits systemic antitumor immune responses. Mechanistically, we identify a tumor cell-centric mode of immune remodeling and further show that the dendritic core actively governs not only small-molecule encapsulation, but also antibody retention and triggered release. Together, this work establishes a materials strategy for overcoming extracellular–intracellular delivery mismatch in combination immunotherapy. Graphical AND-gated dual-responsive nanogel enables spatiotemporally sequential extracellular delivery of aPD-1 and intracellular delivery of GSK3787, thereby overcoming the extracellular–intracellular delivery mismatch and synergistically remodeling the tumor immune microenvironment for enhanced cancer immunotherapy.