光动力疗法（PDT）是癌症治疗的一种有前途的策略。然而，激活光的穿透性较差和低靶点特异性严重阻碍了PDT的临床应用。在此，我们设计并构建了一种具有内外响应的尺寸可控纳米系统（UPH），以提高生物安全性进行深层PDT。为了获得量子产率最佳的纳米颗粒，通过自组装的层层法合成了一系列不同厚度的核-壳纳米颗粒（UCNP@nPCN），将多孔性卟啉配位网络（PCN）结合到上转换纳米颗粒（UCNPs）表面，然后在具有优化厚度的纳米颗粒表面涂覆透明质酸（HA）以形成UPH颗粒。在透明质酸的帮助下，UPH纳米颗粒能够在肿瘤部位优先富集，并通过CD44受体特异性内吞作用以及癌细胞中透明质酸酶的响应性降解。随后，在被强穿透性的980纳米近红外光（NIR）激活后，UPH纳米颗粒可以有效地将氧转化为基于荧光共振能量转移（FRET）效应的强氧化反应性氧种，从而显着抑制肿瘤生长。体外和体内的实验结果表明，这种双响应型纳米颗粒成功地实现了深部癌症的光动力疗法，副作用微乎其微，具有潜在的临床转化研究的巨大潜力。

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, a poor tissue penetration of activation light and low target specificity seriously hindered the clinical application of PDT. Here, we designed and constructed a size-controllable nanosystem (UPH) with inside-out responsive for deep PDT with enhanced biosafety. To obtain nanoparticles with the best quantum yield, a series of core-shell nanoparticles (UCNP@nPCN) with different thicknesses were synthesized by a layer-by-layer self-assembly method to incorporate a porphyritic porous coordination network (PCN) onto the surface of upconverting nanoparticles (UCNPs), followed by coating with hyaluronic acid (HA) on the surface of nanoparticles with optimized thickness to form the UPH nanoparticles. With the aid of HA, the UPH nanoparticles were capable of preferentially enriching in tumor sites and specific endocytosis by CD44 receptors as well as responsive degradation by hyaluronidase in cancer cells after intravenous administration. Subsequently, after being activated by strong penetrating 980 nm near-infrared light (NIR), the UPH nanoparticles efficiently converted oxygen into strongly oxidizing reactive oxygen species based on the fluorescence resonance energy transfer (FRET) effect, thereby significantly inhibiting tumor growth. Experimental results in vitro and in vivo indicated that such dual-responsive nanoparticles successfully realize the photodynamic therapy of deep-seated cancer with negligible side effects, which showed great potential for potential clinical translational research.