Recently, Zhai Guangxi and Yang Xiaoye’s group at the School of Pharmaceutical Sciences has published a research paper entitled “Oxygen-boosted biomimetic nanoplatform for synergetic phototherapy/ferroptosis activation and reversal of immune-suppressed tumor microenvironment” in the international journal Biomaterials (TOP 1, Chinese Academy of Sciences). Professor Zhai Guangxi and associate researcher Yang Xiaoye are the co-corresponding authors. PhD student He Zhijing is the first author. And Shandong University is the independent corresponding author affiliation.

Scheme 1. Schematic illustration showing the structure and MMP-2 sensitivity of MP@CH/BSA NP (A) and its in vivo performance (B).

Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform was fabricated to precisely deliver photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. As illustrated in Scheme 1A, bovine serum albumin (BSA) was utilized as the carrier of chlorin e6 (Ce6, C) and hemin (H), forming Ce6/hemin co-loaded BSA nanoparticle (CH/BSA NP). M1 macrophage membrane with tumor-affinity was modified with PEP20 to form PEP20-modified membrane (MP), which was utilized to camouflage CH/BSA NP, obtaining MP@CH/BSA NP. A matrix metalloproteinase-2 (MMP-2) sensitive peptide sequence (-PLGPAG-, L) was adopted as the linker between PEP20 and membrane, which was designed to be cleaved by the overexpressed MMP-2 in TME (Scheme 1A); the released PEP20 was expected to block the CD47-SIRPα interaction in TME. Hemin’s catalase-mimetic activity alleviated TME hypoxia and enhanced PDT. The nanoplatform activated ferroptosis via both classical (deregulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe²⁺ overload) modes. The research observed that Ce6 enhanced ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity was reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 was revealed for the first time to sensitize ferroptosis by down-regulating system Xc^-. In summary, this work shed new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.

In recent years, Professor Zhai Guangxi’s group has made a series of research achievements in targeted drug delivery, tissue infiltration and immunotherapy of tumors, which were successively published in Nano Today, Biomaterials, Journal of Controlled Release, Materials Today Nano, Journal of Nanobiotechnology and other international nano biological and pharmaceutical journals. This work is supported by National Science and Technology Major Special Project-Major New Drug Creation, Natural Science Foundation of China, Shandong Natural Science Foundation, Shandong Provincial Program of Taishan Industrial Experts and the Fundamental Research Funds of Shandong University.