**4. Conclusions**

OA is mainly caused by trauma induced by an external force or cartilage damage ac-cumulated during aging. This study provided new insights into the therapeutic effects of intra-articular injection of Hyt-loaded chitosan nanoparticles embedded into thermosensitive hydrogels (Hyt@tgel10). The hydrogel exhibited a sol-gel transition behavior and a gelation time consistent with its therapeutic application. Moreover, Hyt released from hydrogel was able to protect chondrocytes from ROS damage and to revert the activation of inflammatory factors, limiting, in an in vitro model, the vicious cycle typical of OA progression. Hence, it can be concluded that the formulated hydrogel injection could be proposed for the efficient and sustained Hyt delivery for OA treatment. The next step would be the extraction of "added-value" bioactive polyphenols from by-products of the olive industry, in order to develop a green delivery system able not only to enhance human wellbeing but also to promote a sustainable environment.

**Author Contributions:** Conceptualization, A.V., R.C. and A.C.; investigation, A.V., R.C., F.D.C. and I.D.L.; writing—original draft preparation, A.V. and R.C.; writing—review and editing, M.B. and A.C.; supervision, M.B. and A.C.; funding acquisition, M.B., G.P. and A.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was financially supported by the PON 03 PE\_00110\_1/ptd1\_000410 Titolo: Sviluppo di nanotecnologie Orientate alla Rigenerazione e Ricostruzione tissutale, Implantologia e Sensoristica in Odontoiatria/oculistica (SORRISO); POR Campania FESR 2014\_2020 "Tecnologie abilitanti per la sintesi eco-sostenibile di nuovi materiali per la restaurativa dentale"—ABILTECH; EU funding within the Horizon 2020 Program, under the MSCA-RISE 2016 Project "VAHVISTUS" (Grant 734759); POR 2014–2020 FESR MISE Prog. n.F/200004/01-02/X45: Micro-Poli, Titolo: Micronanodispositivi veicolanti polifenoli isolati da scarti della filiera olivicola come nuovi integratori alimentari; Fondazione Cariplo, "grant no. 2018-1001", Economia Circolare-Ricerca per un Futuro Sostenibile" program, "High added-value bioactive polyphenols recovered from waste of olive oil production" research project.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available in the article.

**Acknowledgments:** The authors gratefully acknowledge Orsolina Petillo for her assistance with cell culture (IRET-CNR).

**Conflicts of Interest:** The authors declare no conflict of interest.
