Due to the complex biological barrier, drug delivery based on nanoparticles is faced with the challenge of imprecise targeted delivery and low bioavailability of drugs. Here, Nicholas A. Peppas of the University of Texas at Austin and Gao Huile of Sichuan University designed core-shell nanoparticles (DLTPT) with targeted cascade and dual drug loading, which were composed of a hyaluronic acid-modified adriamycin (HA-DOX) shell targeting CD44 and a core-loaded LND dimer (LTPT) targeting mitochondrial triphenylphosphine derivatives. 









Due to the effect of tumor homing and negatively charged hyaluronic acid, DLTPT showed prolonged blood circulation time and effectively gathered in the tumor site. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in a decrease in particle size, a shift from negative charge to positive charge, and increased tumor penetration and internalization. The degradation of HA-DOX further accelerates the release of DOX and exposes the positively charged core of LTPT to achieve rapid endosome escape and mitochondrial targeted delivery of LND. It is worth noting that when DLTPT is used in combination with anti-PD-L1, tumor growth is inhibited, which induces an immune response to tumor metastasis. 









In this paper, dual-drug chemotherapy and immunotherapy were successfully combined to maximize the therapeutic effect. This intelligent nano-platform overcomes the biological obstacles of chemotherapy, including prolonged blood circulation time, enhanced osmosis and retention, increased cell uptake, and delivery and release of targeted organelles, thereby delivering DOX and LND to specific sites simultaneously. The synergism of DOX and LND enhanced the anti-tumor effect and promoted the production of CTL. In addition, the combination of DLTPT and anti-PD-L1 in vivo can trigger a stronger immune response, thus inhibiting the growth and metastasis of primary tumors. This strategy is of great value for the development of advanced cascade targeting nanosystems to achieve effective drug delivery and enhance immune response.