Abstract
Interstitial hypertension and extracellular matrix (ECM) barriers imposed by cancer-associated fibroblasts (CAFs) at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses (OVs) as well as their efficacy in infecting and eradicating tumor cells. Herein, a stable, controllable, and easily prepared hydrogel was developed for employing a differential release strategy to deliver OVs. The oncolytic herpes simplex virus-2 (oH2) particles were loaded within sodium alginate (ALG), together with the small molecule drug PT-100 targeting CAFs. The rapid release of PT-100 functions as an anti-CAFs agent, reducing ECM, and alleviating interstitial pressure at the tumor site. Consequently, the delayed release of oH2 could more effectively invade and eradicate tumor cells while also facilitating enhanced infiltration of immune cells into the tumor microenvironment, thereby establishing an immunologically favorable milieu against tumors. This approach holds significant potential for achieving highly efficient oncolytic virus therapy with minimal toxicity, particularly in tumors rich in stromal components.
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