Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light‐triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H2O2) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC‐PAMAM) are coassembled with reactive‐oxygen‐species‐responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light‐triggered thermal effect that is able to decompose H2O2 into O2, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen‐mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC‐PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light‐triggered vesicles with both self‐supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.

Intervertebral disc degeneration (IDD) is frequently caused by gradual pathological changes inside intervertebral discs (IVDs) and progressive fibrosis. MicroRNA‐29 (miR‐29) family possesses potent fibrosis suppression capability, but their application for treatment of chronic IDD is limited due to lack of suitable local delivery systems. In this report, given various overexpressed matrix metalloproteinases (MMPs) during IDD, injectable MMP‐degradable hydrogels encapsulating MMP‐responsive polyplex micelles are developed for sustained and bioresponsive delivery of miR‐29a into nucleus pulposus cells via a two‐stage process. Cationic block copolymers are designed to complex miR‐29a, and subsequently mixed with the poly(ethylene glycol) (PEG) gelation precursors and MMP‐cleavable peptide cross‐linkers for in situ formation of polyplex micelle‐encapsulated hydrogels in the diseased IVDs. In the presence of MMPs, the polyplex micelles are first released by MMP cleavage of the hydrogels, and subsequently, MMPs‐responsive detachment of PEG shells from polyplex micelles contributes to efficient cellular uptake and endosomal escape. MiR‐29a is demonstrated to effectively silence the expression of MMP‐2, inhibit the fibrosis process, and reverse IDD in animal models through blocking the β‐catenin translocation pathway from the cytoplasm to the nucleus. This two‐stage bioresponsive local miRNA delivery system represents a novel and promising strategy for the treatment of chronic IDD.

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The improved antioxidant system of cancer cells renders them well-adaptive to the intrinsic oxidative stress in tumor tissues. On the other hand, cancer cells are more sensitive to elevated tumor oxidative stress as compared with normal cells due to their deficient reactive oxygen species-eliminating systems. Oxidation therapy of cancers refers to the strategy of killing cancer cells through selectively increasing the oxidative stress in tumor tissues. In this article, to amplify the oxidation therapy, we develop integrated nanoparticles with the properties to elevate tumor oxidative stress and concurrently suppress the antioxidative capability of cancer cells. The amphiphilic block copolymer micelles of poly(ethylene glycol)-b-poly[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)ethyl methacrylate] (PEG-b-PBEMA) are integrated with palmitoyl ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules at pharmacologic concentrations serve as a prooxidant to upregulate the hydrogen peroxide (HO) level in tumor sites and the PBEMA segment exhibits HO-triggered release of quinone methide for glutathione depletion to suppress the antioxidative capability of cancer cells, which synergistically and selectively kill cancer cells for tumor growth suppression. Given the significantly low side toxicity against normal tissues, this novel integrated nanoparticle design represents a novel class of nanomedicine systems for high-efficiency oxidation therapy with the potentials to be translated to clinical applications.

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