Targeted Reprogramming of Vitamin B3 Metabolism as a Nanotherapeutic Strategy towards Chemoresistant Cancers

Adv Mater. 2023 Sep;35(36):e2301257. doi: 10.1002/adma.202301257. Epub 2023 Jul 23.


Cancer-associated fibroblasts (CAFs) promote cancer stem cell (CSC)-mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, Gemini-like homotypic targeting nanoparticles (NPs) are designed for two-pronged CAF transformation and cancer cell elimination. The CAF-targeted NPs couple vitamin B3 metabolic reprogramming to epigenetic modulation of secreted pro-stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first-line chemotherapeutics, a single dose of hydrogel co-delivering the Gemini-like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long-term protection against tumor rechallenge. This study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance.

Keywords: cancer-associated fibroblast remodeling; chemoresistant cancers; gemini-like nanoparticles; hydrogels; vitamin B3 metabolic reprogramming.

MeSH terms

  • Animals
  • Antineoplastic Agents* / metabolism
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cancer-Associated Fibroblasts* / metabolism
  • Cancer-Associated Fibroblasts* / pathology
  • Cell Line, Tumor
  • Mice
  • Neoplasms* / drug therapy
  • T-Lymphocytes, Cytotoxic
  • Tumor Microenvironment
  • Vitamins / metabolism
  • Vitamins / pharmacology


  • Antineoplastic Agents
  • Vitamins